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

Study Overview
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Brief Summary
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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
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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: The rate and severity of COPD exacerbations over 12 months Incidence and severity of metoprolol-related side effects including those that require cessation of drug 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. Hospitalizations 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 All-cause mortality Secondary subgroup analyses for 1) cardiovascular risk based on Personal HEART Score and 2) age greater versus less than 65.

Official Title
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Beta-Blockers for the Prevention of Acute Exacerbations of COPD

Conditions
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Pulmonary Disease, Chronic Obstructive

Intervention / Treatment
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* Drug: Metoprolol succinate
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female subjects, ≥ 40 and less than 85 years of age 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). Cigarette consumption of 10 pack-years or more. Patients may or may not be active smokers. 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: 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. 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. 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. Current tachy or brady arrhythmias requiring treatment Presence of a pacemaker and/or internal cardioverter/defibrillator Patients with a history of second or third degree (complete) heart block, or sick sinus syndrome 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) Resting heart rate less than 65 beats per minute, or sustained resting tachycardia defined as heart rate greater than 120 beats per minute. Resting systolic blood pressure of less than 100mm Hg. 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) Critical ischemia related to peripheral arterial disease. Other diseases that are known to be triggered by beta-blockers or beta-blocker withdrawal including myasthenia gravis, periodic hypokalemic paralysis, pheochromocytoma, and thyrotoxicosis 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. Hospitalization for uncontrolled diabetes mellitus or hypoglycemia within the last 12 months. Patients with cirrhosis A clinical diagnosis of bronchiectasis defined as production of > one-half cup of purulent sputum/day. 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).

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 84 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Metoprolol succinate<br>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). | Drug: Metoprolol succinate<br>* Extended release Metoprolol succinate<br>* Other names: Toprol XL;|
| Placebo Comparator: Placebo<br>Matched placebo | Other: Placebo<br>* Matching placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Acute Exacerbations of COPD | Number of acute exacerbations of COPD - rate per person-year | 1 year | 
| Number of Emergency Department Visits Resulting From Acute Exacerbations of COPD | Number of Emergency Department visits resulting from acute exacerbations of COPD - rate | 1 year | 
| Number of Hospital Admissions Resulting From Acute Exacerbations of COPD | Number of hospital admissions resulting from acute exacerbations of COPD - rate | 1 year | 
| 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. | 14 months | 
| 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 | 12 months | 
| All-cause Mortality | All-cause mortality count | 1 year | 
| 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). | 1 year | 
| 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. | 1 year | 
| Forced Expiratory Volume in 1 Second (FEV1) | Change in FEV1 % Predicted from baseline to visit day 336 as assessed by spirometry | 1 year | 
| 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. | Baseline, 1 year | 
| 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. | Baseline, 1 year | 
| St. George's Respiratory Questionnaire (SGRQ) | 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. | Baseline, 1 year | 
| 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. | Baseline, 1 year | 
| 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). | 1 year | 
| Acute Exacerbations of COPD and MACE | MACE defined by cardiovascular death, hospitalization for myocardial infarction, heart failure, or stroke | 12 months | 
| Short Form Health Survey (SF-36) Physical Function Scale | 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. | 1 year | 
| Short Form Health Survey (SF-36) Role Functioning - Physical 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 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. | 1 year | 
| Short Form Health Survey (SF-36) Role Functioning - Emotional 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 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. | 1 year | 
| Short Form Health Survey (SF-36) Energy/Fatigue 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 Energy/Fatigue Scale includes 4 items. Items are transformed to a score with a range of 0-100. | 1 year | 
| Short Form Health Survey (SF-36) Emotional Well-being 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 Emotional Well-being Scale includes 5 items assessing emotional wellbeing. Items are transformed to a score with a range of 0-100. | 1 year | 
| Short Form Health Survey (SF-36) Social Functioning 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 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. | 1 year | 
| 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. | 1 year | 
| Short Form Health Survey (SF-36) General Health 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 General Health Scale includes 4 items assessing personal evaluations of health. Items are transformed to a score with a range of 0-100. | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic Obstructive Pulmonary Disease, COPD, Exacerbation, Lung function, Cardiac, Cardiovascular, Beta blockers, Metoprolol succinate, Smoking