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

Pulmonary Disease, Chronic Obstructive Clinical Trial

Official title:

Beta-Blockers for the Prevention of Acute Exacerbations of COPD

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02587351
• Other study ID #: 1512M81981
• Status: Terminated
• Phase: Phase 3
• Start date: May 1, 2016
• Est. completion date: December 1, 2019

Study information

• Verified date: January 2021
• Source: University of Minnesota
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 532
• Est. completion date: December 1, 2019
• Est. primary completion date: September 1, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 40 Years to 84 Years

Eligibility

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).

Related Conditions & MeSH terms

• Lung Diseases
• Pulmonary Disease, Chronic Obstructive

Intervention

Drug:
• Metoprolol succinate
Extended release Metoprolol succinate

Other:
• Placebo
Matching placebo

Locations

Country	Name	City	State
United States	University of Michigan	Ann Arbor	Michigan
United States	VA Ann Arbor Healthcare System	Ann Arbor	Michigan
United States	University of Maryland Baltimore	Baltimore	Maryland
United States	Birmingham, Alabama VA Medical	Birmingham	Alabama
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Brigham and Women's Hospital	Boston	Massachusetts
United States	NewYork-Presbyterian Brooklyn Methodist Hospital	Brooklyn	New York
United States	The University of Vermont	Burlington	Vermont
United States	Northwestern University	Chicago	Illinois
United States	Cincinnati VA Medical Center	Cincinnati	Ohio
United States	Cleveland Clinic	Cleveland	Ohio
United States	National Jewish Medical & Research Center	Denver	Colorado
United States	New York Presbyterian/Queens	Flushing	New York
United States	University of California, San Francisco-Fresno	Fresno	California
United States	North Florida/South Georgia Veterans Health System	Gainesville	Florida
United States	Cornell University	Ithaca	New York
United States	LA BioMed at Harbor-UCLA Medical Center	Los Angeles	California
United States	HealthPartners Research Foundation	Minneapolis	Minnesota
United States	Veteran's Administration Medical Center	Minneapolis	Minnesota
United States	Louisiana State University	New Orleans	Louisiana
United States	Columbia University	New York	New York
United States	Temple University Lung Center	Philadelphia	Pennsylvania
United States	University of Pittsburgh	Pittsburgh	Pennsylvania
United States	Mayo Clinic	Rochester	Minnesota
United States	University of Utah Health Sciences Center	Salt Lake City	Utah
United States	University of California at San Francisco	San Francisco	California
United States	University of Washington School of Medicine	Spokane	Washington

Sponsors (3)

Lead Sponsor	Collaborator
University of Minnesota	United States Department of Defense, University of Alabama at Birmingham

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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".	1 year
Secondary	Number of Acute Exacerbations of COPD	Number of acute exacerbations of COPD - rate per person-year	1 year
Secondary	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
Secondary	Number of Hospital Admissions Resulting From Acute Exacerbations of COPD	Number of hospital admissions resulting from acute exacerbations of COPD - rate	1 year
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.	14 months
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	12 months
Secondary	All-cause Mortality	All-cause mortality count	1 year
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).	1 year
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.	1 year
Secondary	Forced Expiratory Volume in 1 Second (FEV1)	Change in FEV1 % Predicted from baseline to visit day 336 as assessed by spirometry	1 year
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.	Baseline, 1 year
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.	Baseline, 1 year
Secondary	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
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.	Baseline, 1 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").	1 year
Secondary	Acute Exacerbations of COPD and MACE	MACE defined by cardiovascular death, hospitalization for myocardial infarction, heart failure, or stroke	12 months
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
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.	1 year
Secondary	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