Beta-Blockers for the Prevention of Acute Exacerbations of COPD
Phase: PHASE3
Conditions: Pulmonary Disease, Chronic Obstructive
Sponsor: University of Minnesota

Study Protocol: Beta-Blockers for the Prevention of Acute Exacerbations of COPD 
 
DECEMBER 12, 2017 
 
NCT02587351 
 

 
 
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Beta-Blockers for the Prevention of Acute Exacerbations of COPD 
 
βLOCK-COPD 
 
 
Revised Protocol Version 04 
12 DECEMBER 2017 
 
 
 
 
 
 
 
 
 
 
Revision History 
Revision 
Effective Date 
 - 
27 July 2015 
- 
21 Sept 2015 
v. 01 
20 March 2016 
v.02 
26 August 2016 
v.03 
24 February 2017 
v.04 
12 December 2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Table of Contents 
 
 
Background and Significance  …………………………………………………………..Page 3-6 
 
 
Overall Research Design and Methods 
Overview. ……………………………………………………………………………….Page 6 
Hypothesis……………………………………………………………………………....Page 6 
Specific Aims……………………………………………………...................................Page 6 
Inclusion Criteria……………………………………………………………………….Page 6-7 
Exclusion Criteria…………………………………………..…………………………..Page 7-8 
Outcome Measures……………………………………………………………………..Page 8-10 
Description of Investigational Product, Safety and Dosing Considerations………..Page 10-11 
Study Flow ………………………………………………………………………………...Page 12-18 
Schedule of Study Interventions………………………………………….......................Page 13 
 
Breakdown of Procedures Conducted at each Study ………………….. …………...Page 14-18 
 
Dose adjustment table………………………………………………………….……….Page 16 
 
Additional Design Considerations …………………………………………………….Page18-19 
 
Discontinuation of Study Drug ………………………………………………………..Page 20 
 
Concomitant Therapy…………………………………………………………………..Page 20-21 
 
Unmasking ……………………………………………………………………………...Page 21 
 
Inclusion of Women and Minorities…………………………………………………...Page 21 
 
Statistics…………………………………………………………………………………Page 21-23 
 
Randomization…………………………………………………………………….........Page 24 
 
Study Confidentiality and Privacy …………………………………………………….Page 24 
 
Data Security …………………………………………………………………………...Page 24-25 
 
Clinical Monitoring Plan ………………………………………………………………Page 25-26 
 
Limitations ……………………………………………………………………………...Page 26 
 
Clinical Impact and Future Directions………………………………………………...Page 27  
 
 
References………………………………………………………………………………....…Page 28-31 
 
 
              
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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v.04  Date: 12 DEC 2017 
 
 
 
Beta-Blockers for the Prevention of Acute Exacerbations of COPD 
 
Background and Significance 
Chronic obstructive pulmonary disease (COPD) recently surpassed stroke as the 3rd leading cause of death in 
the United States and accounts for more than $40 billion annually in direct and indirect health care costs.(1, 2)  
COPD affects approximately 6% of civilians and at least 8% of the Veteran population, though the prevalence is 
increasing in both groups, and when Veterans with respiratory complaints are evaluated with spirometry and 
questionnaires rates of COPD may be as high as 43%.(3)  Veterans with COPD also account for significantly 
higher all-cause and respiratory-related inpatient and outpatient health care utilization including number of 
physician encounters, emergency room visits, acute inpatient discharges, total bed days of care, pharmacy costs 
and total costs than those without COPD. Though existing pharmacotherapy can improve symptoms and quality 
of life, and modestly reduce the risk of acute exacerbations, no treatments alter the natural history of the disease 
or improve mortality.  The impact of COPD on the military and Veteran populations is emphasized by the 
recent efforts to develop a joint Veterans Affairs/Department of Defense Clinical Practice Guideline for the 
disease.(4)     
 
COPD is also associated with an increased risk of a number of major comorbid illnesses, most importantly 
cardiovascular disease which complicates diagnosis and management(5).  Despite clear evidence that beta-
blockers markedly reduce cardiovascular risk in patients with and without COPD concerns regarding their 
potential adverse respiratory effects have led to their dramatic underuse in those with the disease.(6, 7)  This 
practice pattern persists despite recent observational data suggesting that beta-blockers may actually improve 
respiratory outcomes in COPD patients.(8-11)  These data require validation and thus the proposed clinical trial 
of beta-blockers to prevent exacerbations of COPD addresses the most important chronic lower respiratory tract 
illness in the United States, will test the efficacy of a novel approach to prevent its most morbid and costly 
consequences, and will provide critical information needed to shape guideline recommendations regarding the 
management of patients with comorbid cardiovascular disease. 
 
The majority of COPD-related morbidity and health-care costs are due to acute exacerbations, particularly those 
requiring hospitalization.(12, 13)  Multiple treatment strategies have been employed to reduce the rate of 
exacerbations, including drugs administered via inhalation such as corticosteroids and bronchodilators as well 
as systemically delivered drugs such as prednisone, azithromycin and roflumilast.(14)  Though each of these 
drugs reduces the rate of exacerbations by approximately 20 percent, little additional benefit is observed when 
they are used in combination and a substantial number of patients suffer frequent events despite ongoing 
maintenance therapy.(15)  There are a number of possible explanations for the failure of available treatments to 
adequately control the disease including the fact that many exacerbations are triggered or made more severe by 
underlying cardiovascular disease.  COPD is associated with up to a 5-fold increase in atherosclerosis and 
cardiovascular disease independent of shared risk factors,(16) and cardiovascular disease is an independent risk 
factor for hospitalization for COPD exacerbations,(17) in-hospital mortality,(18, 19) and long-term 
survival.(20-23) COPD is also associated with systolic and diastolic congestive heart failure  as well as an 
increased risk for arrhythmias which are also associated with COPD exacerbations.(16) 
 
It is well established that beta-blockers reduce mortality in patients with cardiovascular disease most notably 
after myocardial infarction (MI) (7), in the presence of congestive heart failure (24), and in the perioperative 
setting.(25)  However, patients with COPD are often denied these medications because of concerns about 
possible adverse effects of beta-blockade on airway function.(6, 7, 26, 27) This is despite the fact that 

 
 
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cardioselective beta-blockers have no demonstrable effect on lung function regardless of the severity of airflow 
limitation or the presence of absence of bronchodilator reversibility.(26, 27) The current American Heart 
Association/American College of Cardiology guidelines for secondary prevention of coronary disease include 
beta-blockers as a class I intervention in patients with prior MI or acute coronary syndrome or with heart failure 
(28-30) and the Centers for Medicare and Medicaid include beta-blocker use after discharge following MI as a 
hospital performance measure.  COPD has been cited as the primary reason for withholding beta-blockade in up 
to 33% of these patients.(6) 
 
Multiple observational and retrospective studies have indicated that beta-blockers impact outcomes favorably in 
patients with COPD and underlying cardiovascular disease. Gottlieb et al. reviewed the medical records of all 
Medicare patients discharged after acute MI over an 18-month period (n = 210,752) and evaluated survival with 
Social Security records.(7) Of those with COPD, only 22% were given beta-blockers, compared to 34% of the 
population as a whole, but receipt of the drugs was associated with  a 40% reduction in mortality, an effect 
similar to that seen in the entire population.   A second study examined the effect of beta-blockers as compared 
to other antihypertensive agents on all-cause two-year mortality in patients with COPD and found that the drugs  
were associated with a reduced risk of death (hazard ratio=0.57).(31)  Similarly, Quint et al. analyzed data from 
the General Practice Research Database in the United Kingdom and found that initiating beta-blockers prior to 
or after an acute MI in patients with COPD was associated with similarly improved survival over 3 years of 
follow-up.(22) 
 
More recent data suggest that the benefits of beta-blockers may in fact extend to COPD patients without known 
cardiac disease and may also reduce the risk of acute exacerbations.(8, 9, 11, 32-35)  Mancini demonstrated that 
COPD patients at high risk for coronary events who had  an MI, were hospitalized for COPD, or died during the 
study period were less likely to be taking beta-blockers than those who did not suffer these events (17.1% vs. 
24.0%, p<0.0001).(9)  COPD patients at low risk for cardiovascular events who suffered these events were also 
less likely to be taking beta-blockers (7.5% vs. 9.3%, p<0.0001).(9)  In an analysis of 825 patients admitted to 
the University of Alabama Hospital with acute exacerbations of COPD, beta-blocker use was an independent 
predictor of survival to hospital discharge (OR=0.39, 95%CI 0.14-0.99) after adjustment for a variety of factors 
including the presence of cardiovascular disease.(8)  Rutten et al. also reported that the use of beta-blockers was 
associated with a reduced risk of death (OR=0.68, 0.56-0.83) and of acute exacerbation (OR=0.71, 0.60-
0.83).(10)  Subgroup analyses demonstrated similar benefits in patients with versus without overt 
cardiovascular disease. A recent meta-analyses of nine retrospective cohort studies found that the pooled 
relative risk of COPD related mortality secondary to beta-blocker use was 0.69 (95% CI: 0.62-0.78).(11)  
Collectively, these data argue strongly that a prospective trial verifying that beta-blockers are both safe in 
COPD and efficacious to prevent exacerbations could have a major impact on mortality in both the civilian and 
Veteran populations.   
 
The mechanisms by which beta-blockers may reduce exacerbations remain uncertain though several 
explanations are biologically plausible including both respiratory and cardiovascular effects.  First, chronic 
blockade of beta-receptors may up-regulate receptor density in the lungs leading to improved bronchodilation 
with beta-agonists.(36)  Second, murine data suggests that beta-blockers may reduce airway hyper-reactivity, 
inflammation and mucous secretion which may also be of benefit in the COPD airway.(37, 38)  Third, beta-
blockers may blunt the resting tachycardia in COPD (which occurs in up to 40% of patients) and thus improve 
cardiac performance and exercise tolerance leading to reduced symptoms.(39)  Fourth, as we recently reported, 
P wave dispersion, a surrogate for atrial arrhythmias, is  greater in patients with more frequent exacerbations, 
suggesting a causative role for arrhythmias (40) and raising the possibility that  beta blockade may be beneficial 
in prevention.(41)  Lastly, and perhaps most importantly, up to a third or more of acute exacerbations occur in 

 
 
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the absence of pulmonary inflammation and are very likely caused by cardiac events including both clinically 
apparent  and subclinical coronary ischemia for which beta-blockers have clear benefits.(5)   
 
The positive results of these observational studies should be tempered by the fact that they were all 
retrospective and hence subject to bias. Indeed, another recent large prospective study suggested that beta-
blockers increased mortality in oxygen dependent COPD patients (HR 1.19; 95% CI, 1.04-1.37; p = 0.01).(42) 
In contrast however, we analyzed prospectively collected data from the multicenter COPDGene study (43) to 
determine the relationship between the use of beta-blockers and exacerbation, taking into account the propensity 
to prescribe beta-blockers based on the presence of coronary artery disease (CAD), congestive heart failure 
(CHF) and the severity of symptoms and airflow obstruction.(44)  After adjustment for this propensity and for a 
number of other demographic and clinical characteristics, use of beta-blockers was associated with a 
significantly reduced rate of total and severe exacerbations as shown in Figure 1. 
 
Figure 1.  Relationship between beta-blocker use and acute exacerbations.   
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
In those with advanced disease and on home oxygen, use of beta-blockers was again associated with a reduction 
in the rate of total (IRR 0.40, 95%CI 0.24 to 0.67; p=0.001) and severe exacerbations (IRR 0.49, 95%CI 0.25 to 
0.98; p=0.045).  Similar results from previous studies have been confounded by a lower rate of mortality of in 
those receiving beta-blockers suggesting residual healthy user bias.  However, in our analysis no difference in 
deaths was observed between the two groups suggesting this is less likely.  In addition, we observed no 
relationship between the use of other cardioprotective medications including angiotensin converting enzyme 
inhibitors and calcium channel blockers and exacerbations suggesting our observations are class specific. 
 
Shown are adjusted Incidence Risk Ratios (IRR) for total and severe exacerbations occurring during long 
term follow-up in COPDGene patients who were or were not on beta-blocker therapy at enrolment.  
Three models are shown including model 1 labeled beta-blocker and adjusted for age, gender, race, 
smoking burden, body mass index, airflow obstruction, %emphysema on computed tomography, 
coronary artery calcification, presence of congestive heart failure and coronary artery disease, and long 
acting respiratory medications; model 2 labeled beta-blocker (Prescription adj) adjusted for these factors 
and the propensity to be prescribed the drugs; and model 3 labeled beta-blocker (SGRQ and MMRC adj) 
adjusted further for the severity of dyspnea and impairment in quality of life as assessed by these scales.   
All values expressed as Odds Ratios (95% Confidence Intervals). SQRQ = St. George’s Respiratory 
Questionnaire. MMRC = Modified Medical Research Council Dyspnea Scale.  **p<0.01   †p<0.001 

 
 
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In summary, despite multiple non-randomized studies suggesting a potential benefit of beta blockade in COPD 
patients including those without overt cardiovascular disease, the data are not definitive and the drugs continue 
to be underutilized in this population due to persistent safety concerns.  This conundrum cannot be solved 
without a prospective randomized controlled trial.  Therefore, we propose a safety and efficacy study of once-
daily metoprolol succinate versus placebo in COPD patients at risk for acute exacerbation to determine the 
effect of beta-blockade on lung function, dyspnea, quality of life, exercise tolerance and exacerbation risk. 
 
Research Design and Methods 
 
Overview 
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. 
 
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) Combined rate of acute exacerbations and MACE 
7) All-cause mortality 
 
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): 

 
 
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a. Post bronchodilator FEV1/FVC < 70%, 
 
 
b. 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: 
a. Have a history of receiving a course of systemic corticosteroids or antibiotics for respiratory 
problems in the past year, or  
b. Visiting an Emergency Department for a COPD exacerbation within the past year, or 
c. Being hospitalized for a COPD exacerbation within the past year, or  
d. Be using or be prescribed supplemental oxygen for 12 or more hours per day 
5. Willingness to make return visits and availability by telephone for duration of study. 
 
Exclusion Criteria 
1. A diagnosis of asthma as the primary cause of respiratory symptoms as 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 (55, 56) (Table 1).   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
If, after applying the above criteria, investigators are still unsure about the distinction in a specific patient 
bronchodilator testing with inhaled albuterol will be performed and patients with changes in FEV1 > 400 
mL will be excluded.   
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. 
Table 1: Clinical Features Differentiating COPD & Asthma  
 
History 
COPD 
Asthma 
Smoker or ex-smoker 
Nearly all 
Possibly 
Symptom onset < 35 yrs 
Rare 
Common 
Chronic productive cough 
Common 
Uncommon 
Breathlessness 
Persistent and 
progressive 
Variable 
Nighttime waking with 
breathlessness and wheeze 
Uncommon 
Common 
Significant diurnal or day-to-
day variation of symptoms 
Uncommon 
Common 

 
 
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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.  Patients currently on beta blockers including beta blocker eye drops are also excluded.   
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). 
 
Outcome Measures 
The primary endpoint of this study is the time to first occurrence of an acute COPD exacerbation during the 
one-year treatment period. 
 
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 ".(54) 
 
Acute exacerbations will be graded according to the following scale:  
 
 
1. Mild (home management, with or without contacting a health care provider) 
 
2. Moderate (requiring a visit to an Emergency Department) 
 
3. Severe (requiring hospitalization with or without use of non-invasive positive pressure ventilation) 
 
4. Very severe (requiring intubation and mechanical ventilation) 
 
When patients report that they have severe or very severe exacerbation, the hospital records of that encounter 
will be obtained and reviewed. 
 
The end of an exacerbation is when the patient has returned to their clinical baseline and has completed their 
course of antibiotic, oral steroids or combination of oral steroids and antibiotics to treat the exacerbation as 
defined by Anthonisen.(57)  Since some patients may be on chronic steroid therapy or have varying steroid 
taper regimes used to treat an acute exacerbation by their primary physicians, a return to the baseline chronic 
steroid prescription level or end of the corticosteroid taper course will be considered the end of steroid therapy 
for an acute exacerbation.  A relapse of a previous exacerbation will be defined as the complex of respiratory 
symptoms of more than one of the following: cough, sputum, wheezing, dyspnea, or chest tightness with a 
duration of at least three days that recurs and requires re- treatment with antibiotics and/or systemic steroids 
without a return to baseline and within 2 weeks of the start date of a prior treated event.  

 
 
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Secondary endpoints include: 
 
1) The number of acute exacerbations occurring within 12 months of randomization 
 
2) The number of ED visits resulting from acute exacerbations 
 
3) The number of hospital admissions resulting from acute exacerbations 
 
4) The number of hospital days resulting from acute exacerbations 
 
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) Combined rate of acute exacerbations and MACE 
 
7) All-cause mortality 
 
8) The incidence of presumed metoprolol-related side-effects including 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).  Presumed 
metoprolol-related side effects will be specifically queried for and the severity recorded daily by 
participants during the dose titration period described below and at each clinic and phone visit.  The rate 
of discontinuation of study drug due to presumed metoprolol related side effects will also be collected. 
 
9) Quality of life (SF-36, SGRQ and CAT).  The SF-36 is a generic tool to assess overall health status and 
allows comparison between different diseases. SF-36 scores range from 0 to 100 with higher scores 
representing better health status and a Minimal Clinically Important Difference (MCID) that can be 
appreciated by patients of 4(49).  The SGRQ is a respiratory specific health status questionnaire with 
scores ranging from 0 to 100.(50)  A lower score indicates a better health status and the MCID of the 
SGRQ total score is 4. The CAT is a simple, eight item, health status instrument for patients with COPD 
which is highly practical, has robust psychometric properties, and has been shown to be responsive to 
pulmonary rehabilitation and recovery from exacerbation.(51)  Lower scores denote better health status 
and the MCID for the CAT is 2 points. 
 
10) Dyspnea (MMRC and San Diego Shortness of Breath Questionnaire.  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.(45, 58)  The MMRC scale is not optimal as an evaluative instrument to 
measure changes in dyspnea as its broad grades are generally unresponsive responsive to interventions 
but does sub-classify patients well at baseline and has been used to assess dyspnea due to cardiovascular 
disease.  A one point worsening (increase) in the scale would denote a marked worsening of dyspnea.  
The San Diego Shortness of Breath Questionnaire (SOBQ), a 24-item measure that assesses self-
reported shortness of breath while performing a variety of activities of daily living.(47) The MCID for 
this questionnaire is 5.(46, 58). 
 

 
 
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11) Lung function (FEV1) as assessed by spirometry.  Spirometry is the key pulmonary function parameter 
used for the monitoring of COPD severity.  The MCID for changes in FEV1 is approximately 100 
mL.(58)   
 
12) Exercise capacity as assessed by the 6 minute walk distance (6MWD). The 6MWD has been used as a 
simple tool to assess overall exercise tolerance in patients with chronic cardiopulmonary disease 
including COPD.  The MCID for the 6MWD in COPD is approximately 54 meters.(58)  
 
13) Markers of cardiac stretch and systemic inflammation (NT-pro BNP N-terminal prohormone of 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. 
 
Description of the Investigational Product, Safety and Dosing Considerations 
The clinical trial will utilize metoprolol succinate extended release tablets (50 mg) and matching placebo 
manufactured by Temple School of Pharmacy.  Drug and matching placebo will be labeled using blinded 
coding and distributed to the study sites as needed to support enrolment and retention over the 42 months of 
human subject participation.  The planned starting dose for metoprolol succinate extended release is one 50mg 
tablet taken orally daily though patients will undergo a dose titration procedure as outlined below which will 
result in a final dose of 25mg (1/2 of one tablet daily), 50 mg, or 100 mg (two tablets daily).  Matching placebo 
manufactured at Temple University will be administered similarly.  Following completion of the 12 month 
dosing period patients will be weaned off study drug over the following 4 weeks in order to avoid possible 
rebound myocardial ischemia.  The same approach will be used for patients assigned to blinded placebo.  There 
is no plan to seek an indication for metoprolol’s specific use in patients with COPD and the trial will be 
conducted with an FDA IND waiver. 
 
Metoprolol Safety: Prior Studies of Beta-blockers and Effects on Lung Function and Exercise  
A number of studies have examined the safety of a number of beta blockers in patients with COPD though there 
have been no dose ranging studies to specifically determine the optimal dose for the prevention of 
exacerbations.  Typical doses in trials of patients with coronary artery disease, congestive heart failure and 
hypertension range from 12.5 mg to 200 mg (see package insert) and doses in this range are well tolerated by 
patients with COPD including those with moderate to severe disease(59).  The dose titration procedure is 
modeled after the approach used in a pivotal trial of metoprolol succinate in patients with heart failure (60).  In 
that study, in which daily doses of up to 200 mg (mean dose 159 mg once-daily) were used, 10.3% of 1990 
patients assigned to metoprolol succinate extended-release tablets patients discontinued for adverse reactions vs. 
12.2% of placebo patients.  Adverse events that occurred at an incidence of ≥ 1% in the metoprolol succinate 
extended-release tablets group and greater than placebo by more than 0.5% (and regardless of causality) 
included dizziness/vertigo (1.8% vs. 1.0%), bradycardia (1.5% vs. 0.4%) and accident and/or injury (1.4% vs. 
0.8%).  The planned median daily dose of metoprolol in the proposed trial will fall between 50mg and 100mg 
and these as well as a number of other possible drug related side effects will be specifically sought and 
recorded.   
 
Multiple studies demonstrate that in general the effect of cardioselective beta-blockers on lung function is 
minimal whether administered as a single dose or with continued treatment.  A Cochrane analysis revealed that 
cardioselective beta-blockers produced no significant change in FEV1 or respiratory symptoms compared to 
placebo, given as a single dose (-2.05% [95% CI, -6.05% to 1.96%]) or for longer duration (-2.55% [CI, -5.94% 
to 0.84]), and did not significantly affect the FEV1 treatment response to beta2-agonists.(27, 59)  Subgroup 

 
 
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v.04  Date: 12 DEC 2017 
analyses revealed no significant change in results for those participants with severe chronic airways obstruction 
or for those with a reversible obstructive component.   The trials of metoprolol tested single and multiple dosing 
of the drug at doses between 50mg and 200mg daily.  
 
A more recent study of bisoprolol (a cardioselective beta-blocker) titrated to the maximally tolerated dose and 
given for four months in patients with coexistent congestive heart failure and severe COPD did demonstrate a 
modest reduction in FEV1 (70mL, p=0.01 vs. placebo and lower than accepted MCID) but reversibility was not 
impacted and all measures of health status exhibited a consistent non-significant improvement, including the 
Short Form 36 physical and mental component scores (2.6 vs. 0.5 and 0.8 vs. -0.3, respectively), Minnesota 
Living with Heart Failure Questionnaire (-2.5 vs. 3.5) and Chronic Respiratory Questionnaire (0.07 vs. -
0.24).(61)  
 
Two studies have examined the relationship between bisoprolol use and exercise time in patients with COPD 
and though in one dynamic hyperinflation was worsened slightly there was no impact on peak oxygen 
consumption or exercise time.(62, 63) 
 
Selection of Metoprolol Dose and Dose Titration Procedures 
The initial dose of metoprolol and subsequent titration procedures are adapted from the landmark Metoprolol 
CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF) trial which definitively 
demonstrated the safety and efficacy of beta blockade in patients with symptomatic heart failure, a disease that 
similar to COPD had been considered a contraindication to beta-blocker treatment.  That trial demonstrated that 
as compared to placebo, metoprolol CR/XL not only improved survival and reduced the need for hospitalization 
due to worsening heart failure but improved New York Heart Association functional class and had beneficial 
effects on patient well-being.(60)  At the randomization visit, patients were allocated to treatment with 
metoprolol CR/XL or placebo administered once daily. The starting dosage was one 25-mg tablet once per day 
(half of a 25-mg tablet was recommended for patients with NYHA functional class III or IV).  It was 
recommended to double the dosage after each 2-week period to reach the target dosage level of 200 mg/d of 
metoprolol CR/XL or placebo. This regimen could be modified according to the judgment of the investigator 
which was done successfully without compromising the blinding of study drug. If a patient did not tolerate the 
increased dosage of study drug, reduction in dosage was advocated.  In a post hoc analysis, there was no 
difference in the benefit on mortality between patients who ultimately were titrated to a high dose of metoprolol 
(median 192 mg) and those titrated to a lower dose (median 76 mg).  These data suggest that individualized 
dosing based on patient tolerability was appropriate but and titration to a dose above 100 mg may not be 
necessary to derive clinical benefits.(64)  The initial starting dose of metoprolol is based on prior studies in 
patients with COPD suggesting tolerance both with single and continued dosing at comparable doses of the drug 
and other cardioselective beta-blockers.(27, 59, 65-67)  It is anticipated that many patients will tolerate titration 
to the maximal dose of 100mg while some will require a dose reduction to remain on study medication.  This 
approach was used in the previous CCRN trial of azithromycin to prevent exacerbations in which dosing was 
changed to every other day in patients with persistent diarrhea as well as the prior simvastatin trial in which 
three times per week dosing was used in the event of mild muscle discomfort or cramps.    Although guidelines 
and performance measures for the care of post-MI patients clearly indicate that virtually all such patients should 
be treated with beta-blocker therapy, the guidelines do not provide guidance on dosing and thus cannot be used 
to select the optimum dose for the proposed trial.  There are a number of reasons for this uncertainty including 
the fact that the recommendations are derived from evidence accumulated from multiple clinical trials using a 
number of different drugs and with different regimens and that dose-response studies for long term outcomes 
have not been performed.(68, 69)     
 
 

 
 
Page 12 of 31 
v.04  Date: 12 DEC 2017 
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.  The schedule of study events is shown in 
Table 2.  
(Note: screening and randomization visits can be combined as long as all procedures are conducted and 
eligibility can be confirmed.) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
Page 13 of 31 
v.04  Date: 12 DEC 2017 
 
 
 
Table 2.  Schedule of Study Interventions  
 
 
 
 
Assessment 
Screening+ 
(Day 
-14 to -1) 
Randomization+ 
(Day 0) 
Dose 
Titration 
(Days 14 
and 28) 
Dose 
Finalization 
(Day 42) 
Clinic  
Visit 
(Day 
112) 
Clinic  
Visit 
(Day 
224) 
Wean 
IP 
Clinic 
Visit 
 (Day 
336) 
Stop IP 
Clinic 
Visit 
 (Day 
350) 
Close-
out 
Clinic 
Visit  
(Day 
364) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Medical History 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
X@ 
X 
X 
X 
X@ 
X 
X@ 
X 
X 
Safety Laboratory 
Assessments* 
X 
 
 
 
 
 
 
 
 
Questionnaires** 
X 
 
 
 
X 
 
X 
 
 
Troponin 
X 
 
 
 
 
 
 
 
 
NT-pro 
BNP/CRP/fibrinogen 
 
X 
 
 
 
 
X 
 
 
Urine pregnancy 
X 
 
 
 
 
 
 
 
 
Spirometry# 
X 
 
X 
X 
X 
 
X 
 
 
EKG 
X 
 
X 
X 
X 
 
X 
X 
X 
6 Minute Walk 
 
X 
 
 
X 
 
X 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
Drug  Dispensing  
 
X 
X 
X 
X 
X 
X 
 
 
Adverse Event 
Assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
Drug Return and 
Accountability 
 
 
X 
X 
X 
X 
X 
X 
 
Phone Calls Day 2, 3, 15,16, 56, 168, 280, 343, 357, 378 for adverse event assessment 
 
Visit windows +/- 3 days until dose finalization visit then +/- 14 days until Wean IP visit then +/- 3 days until close-out visit 
 
Unscheduled Visits will include medical history, adverse event assessment, and both EKG and spirometry if during titration period until day 42; 
after day 42, the EKG and spirometry are at PI discretion 
 
*Complete blood count, comprehensive metabolic profile including magnesium, AST, ALT, ALP 
 
**Modified Medical Research Council Dyspnea Scale, COPD Assessment Test, St. George Respiratory Questionnaire, SF-36, San Diego Shortness 
of Breath Questionnaire;  Personal HEART Score at screening only 
 
#Pre- & Post-bronchodilator Spirometry at screening, otherwise post- bronchodilator only; not done at day 112 and 336 if patient has had an acute 
exacerbation in the two weeks prior 
 
@ Full physical by physician; other visits may be brief and do not require physician 
 
+   Screening and randomization visits may occur on the same day as long as all procedures are conducted and eligibility can be confirmed. 

 
 
Page 14 of 31 
v.04  Date: 12 DEC 2017 
Visit 1: Day -14 to -1: Clinic Visit for Screening:  
 
1. Informed consent prior to any study procedures. 
 
2. Demographics (including age, gender, smoking history, oxygen use), information regarding where the 
patient might be seen in an emergency department (ED) and/or hospitalized, should this be required during the 
course of the study, primary care physician name and contact information. 
 
3. A medical history and physical examination that includes recording a list of all medications including 
cardiac and respiratory medications, allergies, menopausal status (women), whether the patient has received 
influenza and/or pneumococcal pneumonia vaccination and if so, when, a list of all comorbidities, whether they 
have chronic bronchitis (defined in American Thoracic Society, 1986), previous COPD-related emergency room 
visits and hospitalizations (including whether they have previously required invasive or non-invasive 
mechanical ventilation), a body mass index (BMI) determination, and a resting oxygen saturation on the 
prescribed amount of supplemental O2 being given, if any, or on air, and resting heart rate and resting blood 
pressure measurements.   
 
4. Spirometry will be performed before and 15-30 min after inhalation of two puffs of albuterol (Ferguson, 
2000; Hankinson, 2003), and post bronchodilator FEV1 and FVC will be recorded.  
 
5. A 12 lead surface EKG in the resting state.  
 
6. Quality of life and dyspnea assessment as described above.   
 
7. Laboratory studies to include:  
a. Complete blood count with differential 
b. Comprehensive metabolic panel including blood urea nitrogen, creatinine, AST, ALT, ALP, and 
magnesium levels.   
c. Serum Troponin-I.  Patients with troponin levels above the upper limit of normal suggesting 
recent ischemia will not be eligible for further screening and referred to their primary physician 
or the emergency department for evaluation.  
d. HCG (urine or blood) for pre-menopausal women. 
 
 
Visit 2: Clinic Visit for Randomization at Day 0:  
 
1. Interim medical history, physical exam and adverse event assessment. 
 
2. Basic education about COPD, its treatment and how to recognize acute exacerbations. Patients will also be 
given a diary to collect the daily occurrence of potential metoprolol-related side effects (see Table of side 
effects above) and with recalling acute exacerbations including those that are treated at home, without contact 
with a health care provider. 
 
3. A wallet card indicating that they are participating in the study and stating “This person may be taking the 
beta-blocker: Extended release Metoprolol succinate.  Please carefully consider potential drug interactions and 
contact research staff with any questions”.  The patients will be instructed to contact the clinic coordinator if 
they are given any new medications.   
 

 
 
Page 15 of 31 
v.04  Date: 12 DEC 2017 
4. Assessment of functional capacity and exercise tolerance will be made by asking patients to perform a six 
minute walk test according to standard ATS guidelines.  
 
5. Venipuncture for collection of markers of cardiac stretch and systemic inflammation (NT-pro Brain 
Natriuretic Peptide, hs-C-reactive protein, fibrinogen).  These parameters will be reassessed at the 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.(70) 
 
6. Only those with resting HR greater than or equal to 65 and SBP greater than or equal to 100 will be 
randomized. 
 
7. Subject will be randomized to extended release metoprolol succinate or placebo (see details of 
randomization process below). A dose of 50 mg will be used as starting dose to be followed by dose titration 
protocol as described below (Table 3). 
 
Visits 3 and 4: Phone Calls on Day 2 and 3:  
 
Assessment of potential adverse respiratory events including symptomatic dyspnea, wheezing, chest tightness as 
well as other potential metoprolol-related side effects.  Patients reporting symptoms concerning for significant 
intolerance of study drug may be seen at an unscheduled protocol visit as indicated in table 2 above.  The 
investigator will determine whether study drug should be discontinued or the dose lowered. 
 
Visits 5: Clinic Visit for dose adjustment at 14 days  
 
1. Respiratory symptoms, concomitant medications, and whether any acute exacerbations occurred since the 
randomization visit will be assessed and recorded.  
 
2. Possible metoprolol-related side effects will be assessed and recorded.  If the patient is not tolerating the 
medication based on clinically significant symptoms as judged by the investigator, they will be discontinued 
from study medication or the dose lowered.  If patients are not able to tolerate 25mg of study drug it will be 
discontinued.  
 
3. The patient's self-assessment of compliance with study drug will be recorded, as will a pill count. 
 
4. A repeat 12 lead EKG will be obtained. 
 
5. Pre-menopausal women will be queried about their contraceptive use and pregnancy status.  Those not using 
acceptable birth control will be discontinued from study medication.  
 
6. Spirometry will be performed.  If a patient has a significant decline in FEV1 (defined as drop in post-
bronchodilator of greater than 15% or 200 ml from the baseline pre-bronchodilator value) and the PI 
believes that it is unsafe to continue study drug then it will be discontinued.  
 
7. For those tolerating medication well, dose adjustments of metoprolol or equivalent placebo will be made by 
a blinded investigator based on assessment of symptoms and tolerability according to the dose adjustment 
protocol (Table 3).  The investigator may modify the dose titration based on his/her clinical judgment and 
after consideration of vital signs, pulmonary function tests, and possible drug side effects. 
 
 

 
 
Page 16 of 31 
v.04  Date: 12 DEC 2017 
 
Table 3.  Dose adjustment protocol.  
Visit 
HR (beats/min)* 
SBP (mmHg) 
Instruction 
Enrollment/Randomization >=65 
>=100 
Randomize 
Dose adjustment Visit at 
14 days  
>=70  
>=100 
↑ dose to 100 mg 
90-99 
↔ maintain same dose 
<90  
↓ dose to 25 mg or stop 
50-69 
>= 90 
↔ maintain same dose 
<90  
↓ dose to 25 mg or stop 
<50 
Any 
Stop study drug 
Dose adjustment Visit at 
28 days  
>=70  
>=90 
↔ maintain same dose 
<90 
↓ dose by 1/2 or stop 
50-69 
>=90 
↔ maintain same dose 
<90  
↓ dose by 1/2 or stop 
<50 
Any 
Stop study drug 
Dose Finalization Visit at 
42 days  
>=70 
>=90 
↔ maintain same dose 
<90 
Stop study drug 
50-69 
>=90 
↔ maintain same dose 
<90  
Stop study drug 
<50 
Any 
Stop study drug 
 
*Heart rate from vital signs (not EKG) will be used.  
 
Visit 6 and 7: Phone calls on Day 15 and 16:  
 
Assessment of potential adverse respiratory events including symptomatic dyspnea, wheezing, chest tightness as 
well as other potential metoprolol-related side effects.  Patients reporting symptoms concerning for significant 
intolerance of study drug may be seen at an unscheduled protocol visit as indicated in table 2 above.  The 
investigator will determine whether study drug should be discontinued or the dose lowered.  If patients are not 
able to tolerate 25mg of study drug it will be discontinued. 
 
Visits 8: Clinic Visit for dose adjustment at 28 days:  
 
1. Respiratory symptoms, concomitant medications, and whether any acute exacerbations occurred since the 
randomization visit will be assessed and recorded.  
 
2. Possible metoprolol-related side effects will be assessed and recorded.  If the patient is not tolerating the 
medication based on clinically significant symptoms as judged by the investigator, they will be discontinued 
from study medication or the dose lowered.  If patients are not able to tolerate 25mg of study drug it will be 
discontinued.  
 
3. The patient's self-assessment of compliance with study drug will be recorded, as will a pill count. 
 
4. A repeat 12 lead EKG will be obtained. 
 
5. Pre-menopausal women will be queried about their contraceptive use and pregnancy status.  Those not using 
acceptable birth control will be discontinued from study medication.  
 

 
 
Page 17 of 31 
v.04  Date: 12 DEC 2017 
6. Spirometry will be performed.  If a patient has a significant decline in FEV1 (defined as drop in post-
bronchodilator of greater than 15% or 200 ml from the baseline pre-bronchodilator value) and the PI 
believes that it is unsafe to continue study drug then it will be discontinued.  
 
7. For those tolerating medication well, dose adjustments of metoprolol or equivalent placebo will be made by 
a blinded investigator based on assessment of symptoms and tolerability according to the dose adjustment 
protocol (Table 3). The investigator may modify the dose titration based on his/her clinical judgment and 
after consideration of vital signs, pulmonary function tests, and possible drug side effects. : 
 
Visit 9: Clinic Visit for dose confirmation/finalization at 42 days: 
 
Spirometry and EKG will be obtained in addition to obtaining an interim history, adverse events, and 
concomitant medications. During this visit, it will be confirmed that the subject is on the same dose as at last 
visit and is tolerating medication well. If not, study drug will be stopped.  Drug will be accounted for and 
dispensed.    
 
Visits 10, 12, 14: Phone Call at Day 56, 168 and 280: 
 
Patients will be contacted by regular phone calls between clinic visits and queried about adverse events 
including: 
 
 
1. Whether any acute exacerbations occurred within the previous month/after last contact 
 
 
2. Whether the patient has any possible metoprolol-related side effects (see above) 
 
 
3. Patients with any of these side effects will be assessed for severity, specifically with regard to whether 
the medication should be discontinued and whether an unscheduled visit is needed.  
   
The same issues will be addressed if participants contact the clinical center by phone on their own. 
 
Visit 11: Clinic Visit at Day 112: 
 
Interim history and adverse events will be collected.  A complete history and physical will be obtained at this 
visit. Questionnaires will be administered again and spirometry, 6MWT and EKG will be performed. Drug will 
be accounted for and dispensed.    
 
Visit 13: Clinic Visit at Day 224: 
 
Interim history, heart rate, blood pressure and adverse events will be collected.  Drug will be accounted for and 
dispensed.    
 
Visit 15: Study End and Dose Wean Clinic Visit at Day 336: 
 
Interim history and adverse events will be collected.  A complete history and physical will be obtained at this 
visit. Questionnaires will be administered again and spirometry, 6MWT and EKG will be performed.  Blood 
will be drawn for hsCRP, fibrinogen and NT-pro BNP.  Dose of study drug will be halved at this visit and 
dispensed. 
 

 
 
Page 18 of 31 
v.04  Date: 12 DEC 2017 
Visit 16 and 18: Phone calls at Day 343 and 357: 
 
This call will ascertain any symptoms of beta-blocker withdrawal including palpitations, chest pain, light 
headedness and new or worsening shortness of breath. Patients reporting significant symptoms will be 
unblinded and may be seen at an unscheduled protocol visit as indicated in table 2 above. 
 
Visit 17: Clinic Visit to stop medication at Day 350: 
 
Interim history and adverse events will be collected. A complete history and physical will be obtained to 
investigate any symptoms or signs of beta-blocker withdrawal.  An EKG will be obtained.  Patients with signs 
or symptoms of withdrawal will be unblinded. 
 
Visit 19: In office closeout Clinic Visit at Day 364: 
 
Interim history and adverse events will be collected. A complete history and physical will be obtained to 
investigate any symptoms or signs of beta-blocker withdrawal such as palpitations, arrhythmias, angina or 
myocardial infarction.  An EKG will be obtained.  Patients with signs or symptoms of withdrawal will be 
unblinded. 
 
Visit 20: Phone call closeout Phone call at Day 378:  Confirm vital status and collect interim history 4 weeks 
after last dose of study drug. 
 
Additional Design Considerations 
 
Recruitment and consent 
 
Recruitment for the proposed trial will follow the well established procedures at the participating CCRN 
centers.  Patients at these sites are recruited from the daily clinical practice of the CCRN investigators and their 
colleagues as well as from HIPAA compliant recruitment databases maintained at the majority of the facilities.  
As referral centers for COPD both within and outside the VA system, the CCRN sites care for a large number of 
patients with moderate to severe disease who are likely to meet inclusion and exclusion criteria.  Based on our 
review of the prior azithromycin and simvastatin trials we are confident we have access to adequate numbers of 
patients to complete recruitment within the proposed three year time frame.  Study records from these trials 
indicate that only 15% of enrolled patients were prescribed beta-blockers and as we will recruit a similar 
exacerbation-prone population, we anticipate a comparable number of patients will be excluded based on their 
current prescription for the drugs.  This rate of beta-blocker use is similar to the 11.8% we observed in our 
analysis of patients with moderate to severe COPD enrolled in COPDGene which also supports the feasibility of 
meeting recruitment goals.  We will also exclude patients with absolute indications for beta-blockers including 
myocardial infarction or acute coronary syndrome within the 3 previous years or significant congestive heart 
failure even if such patients are not currently receiving the drugs.  Published data and our COPDGene analysis 
suggests that approximately 15-20% of patients with moderate to severe COPD would meet one or more of 
these criteria and thus would not qualify for participation.  This rate of exclusionary baseline beta-blocker use 
and indication for use is significantly less than the 65-75% rate of prescribed or indicated statin use we observed 
in our prior clinical trial which successfully recruited more than 850 participants in approximately 42 months.  
This provides reasonable assurance that a sufficient number of participants should be able to be recruited for 
this trial and speaks to its clinical and scientific relevance as its conduct will provide important information on 
the role of beta-blockers in a COPD cohort who currently does not meet indications for treatment. 
 

 
 
Page 19 of 31 
v.04  Date: 12 DEC 2017 
Potential COPD study participants will have to be screened for the use of beta-blockers or the necessity to use 
them by established criteria. As we have successfully done previously, medical record review and/or phone 
interviews will be used to screen potential patients before they are scheduled for on-site clinic visit testing to 
improve trial efficiency.  During in clinic screening, subjects will be interviewed in detail about past medical 
history and prior records may be requested and reviewed.  While medical records are not necessary to document 
exacerbation history, they may be requested and reviewed to help determine other eligibility criteria. Absolute 
indications for beta blockade as established by international guidelines include myocardial infarction, acute 
coronary syndrome, percutaneous coronary intervention, or coronary artery bypass surgery within the prior 3 
years and left ventricular dysfunction (ejection fraction < 40%).(29, 30)   
 
An overview of the timing for screening potential study participants for beta-blocker use or need and the flow of 
study assessments and tests for study participants are shown in the Figure 2 below:    
 
 
Figure 2.  Screening Procedures and Timing 
COPD GOLD II-IV at Risk for AECOPD
On beta-
blocker?
yes
yes
Should be on beta-blocker by 
consensus criteria?
Excluded
Satisfies all other entry criteria?
no
Completes all baseline testing
Randomize
Metoprolol 50 mg/day 
and titrated
Placebo 50mg/day 
and titrated
Clinic and phone call assessments: 
12 months
Wash-out visits over 1 month
 
 
Before being enrolled, patients must consent to participate after the nature, scope, and possible consequences of 
the study have been explained in a form understandable to them. After identification of eligible subjects that 
wish to participate, signed informed consent will be obtained by well-trained Clinical Coordinators or a Study 
Investigator using an Institutional Review Board (IRB) approved consent document.   
  
Details of the protocol will be discussed with the participant ensuring adequate time for consideration of the 
protocol (> 24 hours from initial discussion.). These individuals will then be approached with the informed 
consent form.  The risks, benefits and alternatives will be discussed so that the decision to participate in the 
study will be made independently by the participant. 
 
Any potential participants who cannot consent for themselves will be excluded. This includes anyone who will 
be, or will have been, in a stressful, painful, or drugged condition before or during the consent process or 
otherwise lacks the mental capacity to consent for themselves. We will not obtain consent from Legally 
Authorized Representatives (LARs). We will not enroll minors.   
 

 
 
Page 20 of 31 
v.04  Date: 12 DEC 2017 
Informed consent is an ongoing process. Participants will be asked regularly by Clinical Coordinators or a 
Study Investigator if they have questions about the study. Furthermore subjects will be re-consented as 
determined necessary by each participating site’s IRB in conjunctions with protocol amendments, study reports, 
and any other changes that would affect the participant’s decision to stay in the study.  
 
Discontinuation of Study Drug 
 
There are four instances in which the study drug might be discontinued:   
1. Development of symptoms that might represent medication-related side effects. 
 
Prior to beginning the study patients are instructed about what might constitute a metoprolol-related side effect 
and whom they should notify should such symptoms develop.  They are also queried at each clinic visit and 
phone contact about a specific list of possible metoprolol-related side effects.  If potential side effects develop, 
study personnel will assess the severity of the problem and decide whether the study medication should be 
discontinued or reduced in dose.    
 
2. Development of an absolute indication for beta blocker  
 
This includes myocardial infarction, acute coronary syndrome, percutaneous coronary intervention, coronary 
artery bypass surgery or new congestive heart failure with ejection fraction <40%.  In these instances study 
medication will be stopped and the patient referred for appropriate medical treatment. 
 
3. Intercurrent illness 
 
We anticipate that during the one year treatment period some patients will develop medical and/or surgical 
problems that are unrelated to COPD or to a possible metoprolol-related side effect but warrant treatment.  In 
these instances the patient's treating physicians will decide whether the specific problem encountered warrants 
discontinuation of the study medication.  Each patient will carry a wallet card for the duration of the study that 
provides information regarding the study and how unmasking of treatment can be accomplished should the 
indication merit (see below). 
 
4. New prescription of a contraindicated medication 
 
In instances in which the clinic coordinator/PI becomes aware that a patient has been prescribed or has started 
taking a contraindicated medication the study drug will be stopped.  The study drug can be restarted if the 
contraindicated medication is stopped after consultation between the PI and the prescribing physician. 
 
 Concomitant Therapy 
 
 
COPD-related 
 
All concomitant COPD-related medications are permitted in this trial.  This includes: inhaled 
corticosteroids, systemic corticosteroids long acting bronchodilators, short acting bronchodilators, 
phosphodiesterase inhibitors (roflumilast, theophylline), mucolytics, anti-oxidants, chronic antibiotics, and 
leukotriene modifiers.   
 
Non-COPD-related 
 

 
 
Page 21 of 31 
v.04  Date: 12 DEC 2017 
Given the expected age of the patients we will be enrolling many are likely to have one or more medical 
conditions in addition to COPD.  Therapy for these problems will be continued at the direction of each 
patient's treating physician with the exceptions of the medications listed in the exclusion criteria. 
 
Unmasking 
 
Emergency situations may arise in which it is necessary to discontinue the study drug and unmask treating 
physicians, Emergency Department personnel, clinic personnel, or the patient to the assigned treatment.  
Participants will be given a wallet-size card explaining that they are in a research study and that they are 
assigned to take either metoprolol or a matched placebo.  The card will include telephone numbers of their site's 
pharmacy and/or the responsible investigator.  Patients will be instructed to carry the card at all times.   
 
Situations that require unmasking are expected to be rare.  In most emergency situations it will be sufficient to 
have the participant discontinue taking either the drug or the placebo until the event is resolved.  It is possible 
however, that emergency personnel or treating physicians might feel it is necessary to know the medication the 
participant was taking to decide upon a rational course of treatment, or to ensure that other medications are not 
given that might adversely interact with metoprolol.  In such cases the treating medical personnel should call the 
clinic pharmacy and/or responsible investigator.   
 
Adverse events or hypersensitivity reactions may occur which are believed to be definitely or probably 
associated with the use of metoprolol, and which result in discontinuation of the use of the assigned medication 
by the participant.  In such cases, the participant should be informed of the study drug prescription.  The reason 
for this is to provide information to the participant regarding their use of metoprolol in the future.  If the study 
drug is metoprolol, then the participant should be told that there have been indications that he/she is 
hypersensitive or reactive to this drug and use of it in the future should be avoided.  The participant should also 
be informed if the study drug is placebo, so that his/her use of metoprolol in the future will not be restricted. 
 
Such events must be thoroughly and carefully documented, and an Unmasking Report for the event must be 
completed and transmitted promptly to the DCC.  Such events must be reported to the DSMC on at least a 
quarterly basis. 
 
Inclusion of Women and Minorities 
 
The prevalence of at least moderate COPD (defined by spirometry), the number of COPD-related office visits, 
and the COPD-related death rate are lower in minority patients than in Whites, but Blacks have a higher 
prevalence of ED visits and hospitalization.  There are now more COPD deaths in women than men in the 
United States.  The large male predominance in the armed services results in the fact that patients in any study 
that has Veteran's hospitals as enrollment sites will be disproportionately male unless special enrollment 
strategies are employed to assure a more equal gender distribution.  Accordingly, strategies specifically 
targeting enrollment of women from the other sites will be will be needed for this study.  Demographics vary by 
study site but all efforts will be made to recruit subjects of all genders and ethnicity. 
 
Statistics 
 
Sample size and power considerations for this clinical trial are based on the assumption that the primary 
endpoint will be the time to first exacerbation.  The risk of exacerbation and estimated time to first exacerbation 
in the placebo group is based on observations in the control groups of the prior CCRN trials of azithromycin 
and simvastatin of similar design.(71, 72)  The percent of patients suffering an exacerbation in the placebo arm 

 
 
Page 22 of 31 
v.04  Date: 12 DEC 2017 
of the azithromycin trial was 69% compared with 57% in those receiving azithromycin.  In the simvastatin trial 
the probability of patients in the placebo arm suffering an exacerbation was 65% while the probability in those 
taking simvastatin was not statistically different (68%).  The inclusion and exclusion criteria for the proposed 
trial are very similar to these prior studies and thus we anticipate a comparable exacerbation rate.  Prior 
observational studies suggest that beta-blockers may reduce the risk of exacerbation by as much as 30% though 
it is probable that this overestimates the potential benefit due to residual confounding.  We believe a 15% 
relative reduction (65% vs. 55%) in the one year probability of exacerbation is clinically significant and 
plausible and have thus selected that as our hypothesized effect size.   
 
Assumptions:  
 
The basic study design: two groups (metoprolol, placebo), recruitment over a 3-year period, each participant on 
study for 1 year, plus: 
 
1. Two-sided alpha = 0 .05 
2. Power = 90% 
3. Primary Outcome = time to exacerbation (days) 
4. Probability of exacerbation in the placebo group over 1 year: 65% 
5. Probability of exacerbation in the metoprolol group over 1 year: 55% 
6. Equal probability of assignment to either the placebo or beta-blocker group 
 
These assumptions yield a predicted sample size requirement of 912 patients.  Assuming 12% drop out yields a 
final sample size of 1028 patients. 
 
Principal Analysis of the Primary Outcome Measure 
 
All randomized patients will be followed until the end of the study (whether or not they continue to take study 
medications) and the final analysis will be performed on an ‘intention to treat’ basis.  Using this approach, 
patients will be included in the analysis according to the group to which they were randomized.  Baseline 
characteristics in the two treatment arms will be compared using univariate descriptive statistics.   The analyses 
of the time to first COPD exacerbation (and all-cause mortality) will be performed using survival analysis.  
Kaplan-Meier survival curves will be used to describe the probability of remaining outcome-free in the two 
treatment arms as a function of time from randomization into the study.  The curves will be compared using the 
log-rank test statistic.   
 
Principal analysis of the secondary outcome measures 
 
Secondary outcome measures will be assessed at baseline, 4 and 12 months.  COPD exacerbation rates will be 
calculated as events/person-year and compared using a rate ratio. Independence of individual exacerbation 
events will be assured by considering patients to have experienced a new COPD exacerbation if they had been 
off of oral steroids and antibiotics for at least 14 days following their previous exacerbation.(57)   Exacerbation 
rates for each group, and the resultant rate ratio, will be analyzed using negative binomial regression modeling.  
The model will employ time-weighted intention-to-treat analyses with adjustments of the confidence intervals 
for between-subject variation (overdispersion).(73, 74)  This methodology, which implicitly includes a random 
effect for the individual, has been established as the ‘state of the art’ for analysis of COPD exacerbation rates 
and is less subject to bias than other approaches.  Continuous outcome measures, including absolute and percent 
changes in FEV1 and FVC, 6 minute walk distance, dyspnea, and quality of life scores will be analyzed using 
multivariate repeated measures analysis of variance using the SAS Proc Mixed program.  

 
 
Page 23 of 31 
v.04  Date: 12 DEC 2017 
 
Interim Analysis, Stopping Guidelines, Monitoring Boundaries 
 
Participants will be randomized into this study over an estimated period of 3 years.  Each participant will be 
randomized to one year of treatment and thus operationally the study will take 4 years to complete.  A Data and 
Safety Monitoring Committee (DSMC) will meet approximately every 6 months to review recruitment, follow-
up rates, and compliance, safety and efficacy results.  Reviews of endpoint data at such meetings involve the 
problem of multiple statistical testing performed on a set of accumulating data. As a solution to the problem of 
repeated tests, we propose to adopt a group sequential method related to that proposed in the 1970s by O’Brien 
and Fleming.(75)  Such procedures typically require large critical values (or boundaries) early in the trial, but 
these decrease as the trial progresses.  Because of the conservatism early in the trial, the critical value in the 
final analysis is close to the “nominal” critical value.  The specific method we propose is a general approach to 
group sequential testing developed by Lan and DeMets for which neither the number of looks nor the 
increments between looks need to be pre-specified.(76)  Rather, the Lan-DeMets approach requires only 
specification of the rate at which Type I error (which here will be chosen to be alpha = 0.05) will be “spent”.  
This procedure allows “spending” a little of alpha at each interim analysis in such a way that at the end of the 
study, the total Type I error does not exceed 0.05.   
 
We propose to carry out interim formal testing for efficacy at two interim time points when approximately one 
third and two thirds of the expected primary outcome events (first exacerbation) in the placebo group have 
occurred. However, exacerbations will be included in the safety analyses presented to the DSMC beginning 
twelve months after the first patient is randomized and continuing at twelve month intervals until all patients 
have completed follow-up. A final analysis will be conducted at study completion.  Two-sided tests of 
significance will be assumed.   
 
Use of the alpha-spending function approach to sequential monitoring has the advantage that, if necessary, 
additional looks at the data can be accommodated without affecting the overall probability of Type I error 
(alpha).  Thus if recruitment into the trial takes longer than expected, analyses of the data for DSMC meetings 
may occur at information times which are different from those above. 
 
Judgment concerning the continuation or termination of the study will involve not only the level of statistical 
significance observed at the interim analysis, but also the likelihood of achieving significance should enrollment 
continue to the original projected sample size.  As an aid in this assessment, the Data Coordinating Center will 
supplement the group sequential analysis outlined above with calculations of conditional power based on the 
method of stochastic curtailment (also known as futility analysis).(77).  This procedure evaluates the conditional 
probability that a particular statistical comparison will be significant (or not significant) at the end of the trial at 
the alpha  level used in the design, given the hypothesized treatment difference and the endpoint data 
accumulated to date.  Conditional power for the primary endpoint will be computed and provided to the DSMC 
as part of the interim study reports, and will include calculations based on the originally hypothesized treatment 
difference as well as the observed treatment difference up to that point in the trial. 
 
Planned Subgroup Analyses:  Using the approach outlined for primary and secondary analyses, we will perform 
two subgroup analyses for: 1) cardiovascular risk based on Personal HEART Score and 2) age greater versus 
less than 65.  These analyses will primarily be hypothesis generating in nature. 
 
 
 
 

 
 
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Randomization  
 
Randomization will be carried out by linking to the Data Coordinating Center through a website, 
(https://beta.umn.edu or https://betablocker.umn.edu) using a required COPD Clinical Research Network 
(CCRN) User ID and password.   
Randomization cannot occur if required data are missing or if eligibility criteria are not met.  The treatment 
assignment will not be issued until all criteria are met. 
 
Each participant may receive only one randomization assignment.  Randomization is stratified by each 
designated site in each clinical center.  As an example, the Minneapolis clinical center has three sites: the VA 
Hospital in Minneapolis, Health Partners, and the Mayo Clinic.  Separate schedules are created for each.   
 
If all eligibility criteria are met the randomization program will issue a treatment assignment number such as 
‘113’.  This number matches a schedule that is retained in each site's clinical pharmacy, where separate supplies 
of active drug and the placebo are also kept.  The only persons knowing this schedule will be the pharmacist 
and DCC staff.  The actual assignment will only be revealed in cases of emergencies where caregivers need to 
know what drugs the person was taking to provide treatment, or to avoid prescribing other medications that 
might adversely interact with the study drug. Each randomization code number will be associated with either 
metoprolol or placebo.  
 
Active-drug and placebo will be identical in appearance.  Clinic staff will make no attempt to determine the 
treatment assignment except in cases of emergency.  It will be clearly explained to each study participant that 
they will be assigned to use either active drug or placebo, that the treatment assignment is random (i.e., cannot 
be predicted in advance, like the outcome of a coin-flip), and that they should not attempt to discover the 
treatment assignment.  
 
Each time the participant returns for a renewed supply of study drug, the clinic coordinator must request that the 
pharmacist distribute pills for that specific participant’s treatment assignment number, referring to the schedule 
in the pharmacy.  If the participant’s treatment assignment number is lost or forgotten, the information can be 
obtained by contacting the pharmacy or the DCC. 
 
Study Confidentiality and Privacy 
 
Study participants are identified by a unique number with a check digit for data integrity and an enrollment code 
consisting of the first letter of the participant’s last name and the last two digits of their birth year.  No PHI will 
be collected on study case report forms (CRF) or transmitted to the Data Coordinating Center (DCC).  Any 
identifying information that could be classified as PHI will be kept separate from the participant CRFs in a 
secure environment at the clinical center accessible only to study staff allowed access to PHI.  Documents 
which contain PHI requested by the DCC will be properly de-identified prior to transmission so that no PHI can 
be obtained from the records.  Abnormal and clinically important screening test results including laboratory 
findings (serum chemistries, blood count values, cardiac markers) as well as clinically relevant EKG findings 
will be shared with the participant if he/she agrees shared with their primary care provider.  Recommendations 
for referrals to specialist care will also be provided as necessary.    
 
Data Security 
 
The web-based data submission software is Oracle Application Server 11g Release 1. All data transmitted from 
the clinical sites to the DCC and from the DCC to the clinical sites is SSL encrypted. The cryptographic 

 
 
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v.04  Date: 12 DEC 2017 
libraries used for SSL are designed to meet FIPS 140-2 Level 2 certification.  The website is secured by 
individual usernames and strong passwords.  
 
Non-secure ports of all servers are located behind the DCC network firewall and accessible only under the 
following conditions: 1) a workstation physically present in the building and physically connected to the 
network 2) granted system access to the database server 3) a user name and strong password for that database 
server 4) a second username and strong password for database software 5) granted database access to data 
items.  
 
All non-essential ports of the database server and web servers are closed.  Only one secure (HTTPS) port on the 
website server is open outside of the firewall; this port displays the login link to the secured website.   
Clinical site staff may access individual data items for a given participant (only those in their own clinic) for 
review, but they are unable to download any participant data, aggregate it, cross reference an individual’s data, 
or view participant data from another clinical site via the website.  
 
DCC staff will be trained and instructed not to export data to a standalone file, whether to laptops, hard drives, 
thumb drives, CDs, or any other media.   
 
All servers are physically located in a secured room which is accessible only by a key card; currently, only two 
system administrators, one financial administrator, and the Database Administrator have access to this room.  In 
addition, the secured room is located in a secured suite which is also accessible only by key cards given to 
current University of Minnesota employees located in the suite.  The building is locked and accessible only by 
University of Minnesota employees located in the building after business hours and on weekends. 
The security administrator for Oracle RDBMS and Oracle Application Server is the Database Administrator.  A 
network system administrator regularly monitors for occurrences of attempted access to the network by 
unauthorized users. Only the Database Administrator has access to sensitive software passwords. 
On-site backup of study data is performed nightly; off-site backups are taken twice weekly and stored at a 
secure University of Minnesota location, in a locked office in a secure suite.  Additional redundancy is 
accomplished by storing duplicate database data files and control files on a separate server for disaster 
mitigation. 
 
Clinical center staff will have access to participant CRFs and identifying information. DCC staff who will have 
access only to de-identified data which does not contain PHI include the senior statistician, masters level 
statisticians, the Database Administrator, and the Data Quality Control Specialist. Representatives of the 
Department of Defense who are allowed to have access to PHI are eligible to review study records. 
 
Clinical Monitoring Plan:   
 
Clinical trial monitoring to ensure the trial is conducted in compliance with Good Clinical Practices and ICH E6 
will be multifaceted including real time oversight by the local PIs, regular and real time monitoring of entered 
clinical data by staff at DCC, as well as by an independent Data and Safety Monitoring Committee (DSMC) 
which will meet at 6-month intervals by teleconference or in person.  The DSMC will be made up of a lead 
Research Monitor, at least one cardiologist, one pulmonologist and a statistician.  
 
The Research Monitor, Nadia Hansel, MD, MPH is responsible to oversee the safety of the research and report 
observations/findings to the IRB or a designated institutional official. The Research Monitor will review all 
unanticipated problems involving risks to subjects or others associated with the protocol and provide an 
independent report of the event to the IRB. The Research Monitor may discuss the research protocol with the 

 
 
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v.04  Date: 12 DEC 2017 
investigators; shall have authority to stop a research protocol in progress, remove individual human subjects 
from a research protocol, and take whatever steps are necessary to protect the safety and well-being of human 
subjects until the IRB can assess the monitor's report; and shall have the responsibility to promptly report their 
observations and findings to the IRB or other designated official and the HRPO. 
 
 
The DCC will prepare all materials for the DSMC and will schedule meetings and prepare draft agendas.  At 
each of its meetings the DSMC will review: 
• Progress in recruiting 
• By-clinic data on follow-up rates, forms completion, data entry, and adherence to protocol 
• Efficacy: Survival-analyses of time to first exacerbation; rates of exacerbations per person-year as 
specified in the statistical plan for interim analyses 
• Serious adverse events  
• Other data (e.g., changes in lung function, adherence to assigned drug, other drug use) 
 
The DCC will report on Serious Adverse Events (SAEs), with masking of the treatment assignment, to the 
clinical center PIs (to be forwarded to their IRBs), to the DOD Project Office, and to the DSMC.   
 
The DCC will monitor the study to ensure that the: 
• Data are authentic, accurate, and complete. 
• Safety and rights of subjects are being protected. 
• Study is conducted in accordance with the currently approved protocol and any other study agreements, 
GCP, and all applicable regulatory requirements. 
 
The DCC will conduct monthly teleconferences throughout the study to review study enrolment and retention, 
procedures, adherence to protocol, timeliness of data entry, and adverse events including those that may warrant 
protocol changes.   
 
Limitations  
 
As with any clinical trial a major consideration is recruitment which often proves challenging.  Based on our 
prior experience with the azithromycin and simvastatin clinical trials, we anticipate that our targets are readily 
achievable based on a number of factors.  First, allowing three years for recruitment of the full population is in 
line with these two prior studies.  Second, we believe that recruitment for the proposed trial will in fact be 
significantly easier than for the simvastatin trial, which excluded patients with even modest cardiovascular risk 
who should already be prescribed a statin.  By only excluding patients with an absolute indication for beta-
blockers (recent myocardial infarction, coronary artery bypass surgery, percutaneous coronary intervention, and 
congestive heart failure) many patients not eligible for the simvastatin trial will be eligible for the current study.  
Third, each participating center has a history of recruiting well not only for the CCRN trials but for other 
interventional studies in COPD.   
 
There is a possibility that patients will not tolerate metoprolol, forcing drug to be discontinued.  Though we 
anticipate that the inclusion of a protocol for dose reduction will minimize this possibility, this could reduce the 
number of patients continuing on study drug and compromise the probability of detecting a beneficial effect of 
beta-blockers on exacerbations.  We have estimated this drop out to be 12% which is higher than expected 
based on the previously conducted safety studies of beta-blockers in COPD.   
 
 

 
 
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v.04  Date: 12 DEC 2017 
 
 
Clinical Impact and Future Directions 
 
The results of this trial will definitively answer two questions of major public health importance.  First, the 
study will settle the ongoing debate regarding the safety of beta-blockers in patients with COPD.  If proven safe, 
these data will have immediate clinical impact and lead to significant modification of existing guidelines for the 
use of beta-blockers in patients with COPD and coexisting cardiovascular disease.  This could lead to a major 
increase in the prescription of beta-blockers in this population which should in turn improve outcomes.  Second, 
demonstrating the efficacy of beta-blockers in reducing the risk of acute exacerbations would establish an 
entirely new treatment approach for the prevention of these highly morbid and costly events.  It would also 
allow future investigation of the possible role of beta-blockers in the acute treatment of hospitalized patients 
with COPD exacerbations in whom cardiac ischemia and arrhythmias are very common.    
 
 

 
 
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