Simvastatin Therapy for Moderate and Severe COPD (STATCOPE)

• Time to first COPD exacerbation [ Time Frame: up to 37 months ] [ Designated as safety issue: No ]
• Lung function, dyspnea, and quality of life [ Time Frame: up to 37 months ] [ Designated as safety issue: No ]
• Hospitalization rates and healthcare utilization [ Time Frame: up to 37 months ] [ Designated as safety issue: No ]
• Systemic and lung-specific biomarkers of inflammation and procoagulant activity [ Time Frame: up to 37 months ] [ Designated as safety issue: No ]
• Cost-effectiveness of simvastatin therapy for COPD [ Time Frame: up to 37 months ] [ Designated as safety issue: No ]
• Rate of combined cardiovascular events [ Time Frame: up to 37 months ] [ Designated as safety issue: No ]
• The effect of current smoking status on inflammatory biomarker levels and response to simvastatin treatment [ Time Frame: up to 37 months ] [ Designated as safety issue: No ]
• Pharmacogenetics and pharmacoepigenetics of statin therapy in COPD [ Time Frame: one time point within study period ] [ Designated as safety issue: No ]

To determine the effect of daily administration of 40 mgms simvastatin taken for at least 12 months (range 12-36 months) on the frequency of exacerbations of chronic obstructive lung disease (COPD) in patients with moderate to severe COPD who are prone to exacerbations and do not have other indications for statin treatment.

COPD exacerbation is a common complication that significantly contributes to the high morbidity, mortality and costs associated with COPD. COPD exacerbations are associated with heightened lung inflammation that may have systemic implications (e.g., peripheral muscle weakness, cognitive impairment, depression, stroke, acute coronary syndrome, and atherosclerosis). Statins are potent agents that significantly reduce vascular events in patients with increased risks due to prior cardiac or cerebral vascular events and elevated lipid profiles. Statins have pleiotropic effects that extend well beyond their lipid lowering effects and may be potent anti-inflammatory agents. Retrospective data conducted in COPD patients indicate that statin use is associated with markedly decreased rates of COPD hospitalization and stabilization of lung function. Decreases in mortality in COPD due to complications of flu-like illnesses and deaths due to cardiovascular events have also been reported. Inflammatory biomarkers (C-reactive protein and interleukin- 6) are reported to be elevated in moderate to severe COPD patients who are prone to exacerbations. Inflammatory biomarkers (C-reactive protein and interleukin- 6) are reported to be reduced by statin therapy in patients with hyperlipidemia and cardiovascular diseases. Treatments that can effectively lessen the prevalence and severity of COPD exacerbations are desperately needed

• Drug: simvastatin
  40 mgms of simvastatin daily
  Other Name: Zocor
• Drug: Placebo
  Matched placebo pill daily
  Other Name: sugar pill

• Active Comparator: simvastatin
  40 mgms of simvastatin daily
  Intervention: Drug: simvastatin
• Placebo Comparator: placebo
  Matched placebo pill daily
  Intervention: Drug: Placebo

Inclusion Criteria:

1. Male and female subjects, 40-80 years of age.

2. Clinical diagnosis of at least moderate COPD as defined by the GOLD criteria:

   1. Postbronchodilator FEV1/FVC < 70%,
   2. Postbronchodilator 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. Must meet one or more of the following 4 conditions

   1. Be using supplemental O2
   2. Receiving a course of systemic corticosteroids and/or antibiotics for respiratory problems in the past year,
   3. Visiting an Emergency Department for a COPD exacerbation within the past year, or
   4. Being hospitalized for a COPD exacerbation within the past year
5. Willingness to make return visits and availability by telephone for duration of study.
6. Free of active coronary disease
7. Subject with expected life expectancy > 36 months

Exclusion Criteria:

1. Patients who:

   1. are on statin drugs.
   2. should be on statins based on established risk stratification. (Using the ATP-III risk calculator created by the DCC to determine 10 year risk).
2. Documented history of active CHD, such as unstable angina, prior myocardial infarction, stroke, symptomatic peripheral vascular or carotid artery disease, or congestive heart failure within the past 3 months.
3. A diagnosis of asthma.
4. The presence of a diagnosis other than COPD that results in the patient being either medically unstable, or having a predicted life expectancy < 3 years.
5. Special patient groups: prisoners, pregnant women, institutionalized patients
6. 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.
7. Woman using estradiol compounds for contraception. Postmenopausal women on estradiol compounds for hormone replacement therapy will be allowed into the trial.
8. Participants otherwise meeting the inclusion criteria will not be enrolled until they are a minimum of four weeks from their most recent acute exacerbation.
9. A clinical diagnosis of bronchiectasis defined as production of > one-half cup of purulent sputum/day.
10. Participants using niacin, azole antifungals (itraconazole, ketoconazole, posaconazole), fibric acid derivatives, erythromycin, clarithromycin, telithromycin, diltiazem, amlodipine , ranolazine,HIV protease inhibitors (such as indinavir), amiodarone, gemfibrozil, cyclosporine, verapamil, danazol, nefazodone, and red yeast rice extracts are excluded
11. Active liver disease. Active liver disease is defined as ALT, AST as greater than 1.5 times the upper limit of normal.
12. Patients with renal failure defined by serum creatinine greater than 3mg/dl.
13. Alcoholism. Alcoholism is defined as > 35 drinks per week. A drink is defined as one bottle of beer, one 8-ounce glass of wine, or one ounce of hard liquor.
14. Hypersensitivity to HMG CoA reductase inhibitors. Hypersensitivity is defined as an allergic reaction to statin, prior history of myopathy, rhabdomyolysis or previous intolerance to statin use.
15. Participants drinking greater than 4 cups (1qt) of grapefruit juice per day.
16. Participants drinking greater than 3 cups of green tea per day.
17. Diabetics will be excluded. Diabetics are defined by:

1. A CURRENT physician diagnosis of diabetes OR 2. CURRENT use of diabetic meds OR 3. Elevated HbA1c > 6.5% 18. The discretion of the Principal Investigator that the potential participant will not be a reliable study subject to complete the study requirements.