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

NCT02587351 | Terminated Phase 3 Results DMC

• 1 other identifier: 1512M81981
• Study Type: interventional
• Target: 532
• Locations: 1 country
• Sites: 27

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.

Conditions

Pulmonary Disease, Chronic Obstructive

Keywords

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

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (23)

• Number of Acute Exacerbations of COPD

  1 year

• Number of Emergency Department Visits Resulting From Acute Exacerbations of COPD

  1 year

• Number of Hospital Admissions Resulting From Acute Exacerbations of COPD

  1 year

• Hospital Days Resulting From Acute Exacerbations of COPD

  14 months

• Major Adverse Cardiovascular Events

  12 months

Study Arms (2)

Metoprolol succinate

ACTIVE COMPARATOR

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

Placebo

PLACEBO COMPARATOR

Matched placebo

Other: Placebo

Interventions

Metoprolol succinate DRUG

Extended release Metoprolol succinate

Also known as: Metoprolol Succinate ER, Toprol XL

Metoprolol succinate

Placebo OTHER

Matching placebo

Placebo

Eligibility Criteria

• Age: 40 Years - 84 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Minnesota: lead
• United States Department of Defense: collaborator
• University of Alabama at Birmingham: collaborator

Study Sites (27)

Birmingham, Alabama VA Medical

Birmingham, Alabama, 35233, United States

Location

University of Alabama at Birmingham

Birmingham, Alabama, 35294, United States

Location

University of California, San Francisco-Fresno

Fresno, California, 93701, United States

Location

LA BioMed at Harbor-UCLA Medical Center

Los Angeles, California, 90502, United States

Location

University of California at San Francisco

San Francisco, California, 94143, United States

Location

National Jewish Medical & Research Center

Denver, Colorado, 80206, United States

Location

North Florida/South Georgia Veterans Health System

Gainesville, Florida, 32608, United States

Location

Northwestern University

Chicago, Illinois, 60611, United States

Location

Louisiana State University

New Orleans, Louisiana, 70112, United States

Location

University of Maryland Baltimore

Baltimore, Maryland, 21201, United States

Location

Brigham and Women's Hospital

Boston, Massachusetts, 02115, United States

Location

VA Ann Arbor Healthcare System

Ann Arbor, Michigan, 48105, United States

Location

University of Michigan

Ann Arbor, Michigan, 48109, United States

Location

Veteran's Administration Medical Center

Minneapolis, Minnesota, 55417, United States

Location

HealthPartners Research Foundation

Minneapolis, Minnesota, 55440, United States

Location

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

NewYork-Presbyterian Brooklyn Methodist Hospital

Brooklyn, New York, 11215, United States

Location

New York Presbyterian/Queens

Flushing, New York, 11355, United States

Location

Cornell University

Ithaca, New York, 14853, United States

Location

Columbia University

New York, New York, 10027, United States

Location

Cincinnati VA Medical Center

Cincinnati, Ohio, 45220, United States

Location

Cleveland Clinic

Cleveland, Ohio, 44195, United States

Location

Temple University Lung Center

Philadelphia, Pennsylvania, 19140, United States

Location

University of Pittsburgh

Pittsburgh, Pennsylvania, 15213, United States

Location

University of Utah Health Sciences Center

Salt Lake City, Utah, 84132-4701, United States

Location

The University of Vermont

Burlington, Vermont, 05405, United States

Location

University of Washington School of Medicine

Spokane, Washington, 99258, United States

Location

Related Publications (3)

• 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.

  PMID: 35363600 DERIVED

• 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.

  PMID: 31633896 DERIVED

• 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.

  PMID: 27267111 DERIVED

MeSH Terms

Conditions

Pulmonary Disease, Chronic Obstructive; Smoking

Interventions

Metoprolol

Condition Hierarchy (Ancestors)

Lung Diseases, Obstructive; Lung Diseases; Respiratory Tract Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Behavior

Intervention Hierarchy (Ancestors)

Phenoxypropanolamines; Propanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Propanols; Amines

Results Point of Contact

• Title: John Connett
• Organization: University of Minnesota

john-c@umn.edu

612-626-9010

Study Officials

• Mark Dransfield, MD

  University of Alabama at Birmingham

  PRINCIPAL INVESTIGATOR

• John Connett, PhD

  University of Minnesota

  PRINCIPAL INVESTIGATOR

• Stephen Lazarus, MD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 19, 2015
• First Posted: October 27, 2015
• Study Start: May 1, 2016
• Primary Completion: September 1, 2019
• Study Completion: December 1, 2019
• Last Updated: January 25, 2021
• Results First Posted: January 25, 2021

Record last verified: 2021-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (27)