Clinical trial NCT02587351: Beta-Blockers for the Prevention of Acute Exacerbations of Chronic Obstructive Pulmonary Disease
Official title: Beta-Blockers for the Prevention of Acute Exacerbations of COPD
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Pulmonary Disease, Chronic Obstructive
Keywords: Chronic Obstructive Pulmonary Disease
COPD
Exacerbation
Lung function
Cardiac
Cardiovascular
Beta blockers
Metoprolol succinate
Smoking
Lead sponsor: University of Minnesota
Sponsor class: OTHER
Collaborators: name: United States Department of Defense
name: University of Alabama at Birmingham
First posted: 2015-10-27
Enrollment: 532
Sex: ALL
Minimum age (years): 40
Maximum age (years): 84
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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).

Primary outcomes:
measure: Time to First Occurrence of an Acute COPS Exacerbation
timeFrame: 1 year
Secondary outcomes:
measure: Number of Acute Exacerbations of COPD
timeFrame: 1 year
measure: Number of Emergency Department Visits Resulting From Acute Exacerbations of COPD
timeFrame: 1 year
measure: Number of Hospital Admissions Resulting From Acute Exacerbations of COPD
timeFrame: 1 year
measure: Hospital Days Resulting From Acute Exacerbations of COPD
timeFrame: 14 months
measure: Major Adverse Cardiovascular Events
timeFrame: 12 months
measure: All-cause Mortality
timeFrame: 1 year
measure: Incidence of Presumed Metoprolol-related Side-effects
timeFrame: 1 year
measure: Modified Medical Research Council Dyspnea Scale (MMRC)
timeFrame: 1 year
measure: Forced Expiratory Volume in 1 Second (FEV1)
timeFrame: 1 year
measure: Exercise Capacity as Assessed by the 6 Minute Walk Distance (6MWD)
timeFrame: Baseline, 1 year
measure: Markers of Systemic Inflammation
timeFrame: Baseline, 1 year
measure: St. George's Respiratory Questionnaire (SGRQ)
timeFrame: Baseline, 1 year
measure: COPD Assessment Test (CAT)
timeFrame: Baseline, 1 year
measure: San Diego Shortness of Breath Questionnaire (SOBQ)
timeFrame: 1 year
measure: Acute Exacerbations of COPD and MACE
timeFrame: 12 months
measure: Short Form Health Survey (SF-36) Physical Function Scale
timeFrame: 1 year
measure: Short Form Health Survey (SF-36) Role Functioning - Physical Scale
timeFrame: 1 year
measure: Short Form Health Survey (SF-36) Role Functioning - Emotional Scale
timeFrame: 1 year
measure: Short Form Health Survey (SF-36) Energy/Fatigue Scale
timeFrame: 1 year
measure: Short Form Health Survey (SF-36) Emotional Well-being Scale
timeFrame: 1 year
measure: Short Form Health Survey (SF-36) Social Functioning Scale
timeFrame: 1 year
measure: Short Form Health Survey (SF-36) Bodily Pain Scale
timeFrame: 1 year
measure: Short Form Health Survey (SF-36) General Health Scale
timeFrame: 1 year
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Birmingham, Alabama VA Medical
state: Alabama
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Fresno
country: United States
facility: University of California, San Francisco-Fresno
state: California
city: Los Angeles
country: United States
facility: LA BioMed at Harbor-UCLA Medical Center
state: California
city: San Francisco
country: United States
facility: University of California at San Francisco
state: California
city: Denver
country: United States
facility: National Jewish Medical & Research Center
state: Colorado
city: Gainesville
country: United States
facility: North Florida/South Georgia Veterans Health System
state: Florida
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: New Orleans
country: United States
facility: Louisiana State University
state: Louisiana
city: Baltimore
country: United States
facility: University of Maryland Baltimore
state: Maryland
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Ann Arbor
country: United States
facility: VA Ann Arbor Healthcare System
state: Michigan
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Minneapolis
country: United States
facility: Veteran's Administration Medical Center
state: Minnesota
city: Minneapolis
country: United States
facility: HealthPartners Research Foundation
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Brooklyn
country: United States
facility: NewYork-Presbyterian Brooklyn Methodist Hospital
state: New York
city: Flushing
country: United States
facility: New York Presbyterian/Queens
state: New York
city: Ithaca
country: United States
facility: Cornell University
state: New York
city: New York
country: United States
facility: Columbia University
state: New York
city: Cincinnati
country: United States
facility: Cincinnati VA Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Philadelphia
country: United States
facility: Temple University Lung Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Salt Lake City
country: United States
facility: University of Utah Health Sciences Center
state: Utah
city: Burlington
country: United States
facility: The University of Vermont
state: Vermont
city: Spokane
country: United States
facility: University of Washington School of Medicine
state: Washington
Study officials:
affiliation: University of Alabama at Birmingham
name: Mark Dransfield, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Minnesota
name: John Connett, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, San Francisco
name: Stephen Lazarus, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Parekh TM, Helgeson ES, Connett J, Voelker H, Ling SX, Lazarus SC, Bhatt SP, MacDonald DM, Mkorombindo T, Kunisaki KM, Fortis S, Kaminsky D, Dransfield MT. Lung Function and the Risk of Exacerbation in the beta-Blockers for the Prevention of Acute Exacerbations of Chronic Obstructive Pulmonary Disease Trial. Ann Am Thorac Soc. 2022 Oct;19(10):1642-1649. doi: 10.1513/AnnalsATS.202109-1042OC.
citation: Dransfield MT, Voelker H, Bhatt SP, Brenner K, Casaburi R, Come CE, Cooper JAD, Criner GJ, Curtis JL, Han MK, Hatipoglu U, Helgeson ES, Jain VV, Kalhan R, Kaminsky D, Kaner R, Kunisaki KM, Lambert AA, Lammi MR, Lindberg S, Make BJ, Martinez FJ, McEvoy C, Panos RJ, Reed RM, Scanlon PD, Sciurba FC, Smith A, Sriram PS, Stringer WW, Weingarten JA, Wells JM, Westfall E, Lazarus SC, Connett JE; BLOCK COPD Trial Group. Metoprolol for the Prevention of Acute Exacerbations of COPD. N Engl J Med. 2019 Dec 12;381(24):2304-2314. doi: 10.1056/NEJMoa1908142. Epub 2019 Oct 20.
citation: Bhatt SP, Connett JE, Voelker H, Lindberg SM, Westfall E, Wells JM, Lazarus SC, Criner GJ, Dransfield MT. beta-Blockers for the prevention of acute exacerbations of chronic obstructive pulmonary disease (betaLOCK COPD): a randomised controlled study protocol. BMJ Open. 2016 Jun 7;6(6):e012292. doi: 10.1136/bmjopen-2016-012292.