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

This study is currently recruiting participants.
See Contacts and Locations
Verified April 2017 by University of Minnesota - Clinical and Translational Science Institute
Sponsor:
Collaborators:
United States Department of Defense
University of Alabama at Birmingham
Information provided by (Responsible Party):
University of Minnesota - Clinical and Translational Science Institute
ClinicalTrials.gov Identifier:
NCT02587351
First received: October 19, 2015
Last updated: April 21, 2017
Last verified: April 2017
October 19, 2015
April 21, 2017
May 2016
May 2020   (Final data collection date for primary outcome measure)
First occurrence of an acute COPD exacerbation [ Time Frame: 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".
Time to first occurrence of an acute COPD exacerbation [ Time Frame: 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".
Complete list of historical versions of study NCT02587351 on ClinicalTrials.gov Archive Site
  • Number of acute exacerbations of COPD [ Time Frame: 1 year ]
  • Number of Emergency Department visits resulting from acute exacerbations of COPD [ Time Frame: 1 year ]
  • Number of hospital admissions resulting from acute exacerbations of COPD [ Time Frame: 1 year ]
  • Number of hospital days resulting from acute exacerbations of COPD [ Time Frame: 1 year ]
  • Rate of major adverse cardiovascular events (MACE), percutaneous coronary intervention or coronary artery bypass grafting [ Time Frame: 1 year ]
    MACE defined by cardiovascular death, hospitalization for myocardial infarction, heart failure, or stroke
  • All-cause mortality [ Time Frame: 1 year ]
  • Incidence of presumed metoprolol-related side-effects [ Time Frame: 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).
  • Short Form Health Survey (SF-36) [ Time Frame: 1 year ]
    SF-36 is a generic tool to assess overall health status and allows comparison between different diseases.
  • Modified Medical Research Council Dyspnea Scale (MMRC) [ Time Frame: 1 year ]
    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.
  • Forced expiratory volume in 1 second (FEV1) [ Time Frame: 1 year ]
    FEV1 as assessed by spirometry
  • Exercise capacity as assessed by the 6 minute walk distance (6MWD) [ Time Frame: 1 year ]
    The 6MWD has been used as a simple tool to assess overall exercise tolerance in patients with chronic cardiopulmonary disease including COPD.
  • Markers of cardiac stretch, injury and systemic inflammation [ Time Frame: 1 year ]
    troponin-I, pro-NT Brain Natriuretic Peptide, high sensitivity C-reactive protein, and fibrinogen: These parameters will be assessed at screening/randomization and at conclusion of the study to determine if beta-blockade impacts volume status and cardiac performance as well as levels of systemic inflammation that portend overall cardiac risk.
  • St. George's Respiratory Questionnaire (SGRQ) [ Time Frame: 1 year ]
    The SGRQ is a respiratory specific health status questionnaire with scores ranging from 0 to 100. The lower score indicates a better health status.
  • COPD Assessment Test (CAT) [ Time Frame: 1 year ]
    The CAT is a simple, eight item, health status instrument for patients with COPD. Lower scores denote better health status.
  • San Diego Shortness of Breath Questionnaire (SOBQ) [ Time Frame: 1 year ]
    A 24-item measure that assesses self-reported shortness of breath while performing a variety of activities of daily living.
  • Combined rate of acute exacerbations of COPD and MACE [ Time Frame: 1 year ]
    MACE defined by cardiovascular death, hospitalization for myocardial infarction, heart failure, or stroke
  • Serum Biomarkers [ Time Frame: 1 year ]
  • Number of acute exacerbations [ Time Frame: 1 year ]
  • Number of Emergency Department visits resulting from acute exacerbations [ Time Frame: 1 year ]
  • Number of hospital admissions resulting from acute exacerbations [ Time Frame: 1 year ]
  • Number of hospital days resulting from acute exacerbations [ Time Frame: 1 year ]
  • Rate of major adverse cardiovascular events (MACE), percutaneous coronary intervention or coronary artery bypass grafting [ Time Frame: 1 year ]
    MACE defined by cardiovascular death, hospitalization for myocardial infarction, heart failure, or stroke
  • All-cause mortality [ Time Frame: 1 year ]
  • Incidence of presumed metoprolol-related side-effects [ Time Frame: 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).
  • Short Form Health Survey (SF-36) [ Time Frame: 1 year ]
    SF-36 is a generic tool to assess overall health status and allows comparison between different diseases.
  • Modified Medical Research Council Dyspnea Scale (MMRC) [ Time Frame: 1 year ]
    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.
  • Forced expiratory volume in 1 second (FEV1) [ Time Frame: 1 year ]
    FEV1 as assessed by spirometry
  • Exercise capacity as assessed by the 6 minute walk distance (6MWD) [ Time Frame: 1 year ]
    The 6MWD has been used as a simple tool to assess overall exercise tolerance in patients with chronic cardiopulmonary disease including COPD.
  • Markers of cardiac stretch, injury and systemic inflammation [ Time Frame: 1 year ]
    troponin-I, pro-NT Brain Natriuretic Peptide, high sensitivity C-reactive protein, and fibrinogen: These parameters will be assessed at screening/randomization and at conclusion of the study to determine if beta-blockade impacts volume status and cardiac performance as well as levels of systemic inflammation that portend overall cardiac risk.
  • St. George's Respiratory Questionnaire (SGRQ) [ Time Frame: 1 year ]
    The SGRQ is a respiratory specific health status questionnaire with scores ranging from 0 to 100. The lower score indicates a better health status.
  • COPD Assessment Test (CAT) [ Time Frame: 1 year ]
    The CAT is a simple, eight item, health status instrument for patients with COPD. Lower scores denote better health status.
  • San Diego Shortness of Breath Questionnaire (SOBQ) [ Time Frame: 1 year ]
    A 24-item measure that assesses self-reported shortness of breath while performing a variety of activities of daily living.
Not Provided
Not Provided
 
Beta-Blockers for the Prevention of Acute Exacerbations of Chronic Obstructive Pulmonary Disease
Beta-Blockers for the Prevention of Acute Exacerbations of COPD
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.

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)(45) and San Diego Shortness of Breath Questionnaire (46, 47), exercise tolerance as measured by six minute walk test (6MWD)(48), and quality of life as assessed by the Short Form 36 (49), St. Georges Respiratory Questionnaire (SGRQ)(50) and COPD Assessment Test (CAT)(51) and Personal HEART Score (52).
  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.

Interventional
Phase 3
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Participant, Care Provider, Investigator, Outcomes Assessor
Primary Purpose: Treatment
Pulmonary Disease, Chronic Obstructive
  • Drug: Metoprolol succinate
    Extended release Metoprolol succinate
    Other Names:
    • Metoprolol Succinate ER
    • Toprol XL
  • Other: Placebo
    Matching placebo
  • Active Comparator: 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).
    Intervention: Drug: Metoprolol succinate
  • Placebo Comparator: Placebo
    Matched placebo
    Intervention: Other: Placebo
Bhatt SP, Connett JE, Voelker H, Lindberg SM, Westfall E, Wells JM, Lazarus SC, Criner GJ, Dransfield MT. β-Blockers for the prevention of acute exacerbations of chronic obstructive pulmonary disease (βLOCK COPD): a randomised controlled study protocol. BMJ Open. 2016 Jun 7;6(6):e012292. doi: 10.1136/bmjopen-2016-012292.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
1028
May 2020
May 2020   (Final data collection date for primary outcome measure)

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).
Sexes Eligible for Study: All
40 Years to 84 Years   (Adult, Senior)
No
Contact: Mark Dransfield, MD mdrans99@uab.edu
Contact: Sarah Lindberg, MPH 612-626-9011 slindberg@umn.edu
United States
 
 
NCT02587351
PR140170
Yes
Not Provided
Plan to Share IPD: No
University of Minnesota - Clinical and Translational Science Institute
University of Minnesota - Clinical and Translational Science Institute
  • United States Department of Defense
  • University of Alabama at Birmingham
Principal Investigator: Mark Dransfield, MD University of Alabama at Birmingham
Principal Investigator: John Connett, PhD University of Minnesota - Clinical and Translational Science Institute
Principal Investigator: Stephen Lazarus, MD University of California, San Francisco
University of Minnesota - Clinical and Translational Science Institute
April 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP