Pulmonary Disease, Chronic Obstructive
Conditions
Keywords
Chronic Obstructive Pulmonary Disease, COPD, Exacerbation, Lung function, Cardiovascular, Smoking, Statins, Simvastatin
Brief summary
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.
Detailed description
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
Interventions
DRUGsimvastatin
40 mgms of simvastatin daily
DRUGPlacebo
Matched placebo pill daily
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Canadian Institutes of Health Research (CIHR)
Ottawa Hospital Research Institute
University of Minnesota
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to 80 Years
Healthy volunteers
No
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(forced expiratory volume at one second)/FVC(forced vital capacity) \< 70%, 2. Postbronchodilator FEV1 (forced expiratory volume at one second) \< 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 oxygenate 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 (Chronic Obstructive Pulmonary Disease) 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 (Adult Treatment Panel) to determine 10 year risk. 2. Documented history of active coronary heart disease, 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 (alanine aminotransferase), AST (aspartate aminotransferase) 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 (3-hydroxy-3-methylglutaryl-coenzyme A) 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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Rates of COPD Exacerbations | up to 37 months |
Secondary
| Measure | Time frame |
|---|---|
| Time to First COPD Exacerbation | up to 37 months |
| Change in FEV1 (% Pred) From Baseline to Last Measure | Baseline, last measure at up to 37 months |
| Acute Exacerbation COPD Hospitalization Rates (Events/Patient Year) | up to 37 months |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Simvastatin 40 mgms of simvastatin daily
Simvastatin: 40 mgms of simvastatin daily | 433 |
| Placebo Matched placebo pill daily
Placebo: Matched placebo pill daily | 452 |
| Total | 885 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 28 | 30 |
| Overall Study | Lost to Follow-up | 3 | 5 |
| Overall Study | Withdrawal by Subject | 16 | 20 |
Baseline characteristics
| Characteristic | Simvastatin | Total | Placebo |
|---|---|---|---|
| Acute COPD Exacerbation requiring Hospitalization or ED visit within previous 12 mo No | 217 participants | 431 participants | 214 participants |
| Acute COPD Exacerbation requiring Hospitalization or ED visit within previous 12 mo Yes | 216 participants | 454 participants | 238 participants |
| Age, Continuous | 62.2 years STANDARD_DEVIATION 8.5 | 62.2 years STANDARD_DEVIATION 8.4 | 62.3 years STANDARD_DEVIATION 8.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 11 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 429 Participants | 874 Participants | 445 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| FEV1/FVC (forced expiratory volume at one second/forced vital capacity) | 0.44 Ratio STANDARD_DEVIATION 0.13 | 0.44 Ratio STANDARD_DEVIATION 0.13 | 0.44 Ratio STANDARD_DEVIATION 0.13 |
| FEV1 (% Predicted) | 41.5 percent predicted STANDARD_DEVIATION 17.8 | 41.6 percent predicted STANDARD_DEVIATION 17.7 | 41.6 percent predicted STANDARD_DEVIATION 17.6 |
| Post-bronchodilator FEV1 (forced expiratory volume at one second) | 1.19 liters (L) STANDARD_DEVIATION 0.58 | 1.19 liters (L) STANDARD_DEVIATION 0.57 | 1.19 liters (L) STANDARD_DEVIATION 0.56 |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 5 Participants | 3 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 99 Participants | 190 Participants | 91 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 13 Participants | 11 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 328 Participants | 674 Participants | 346 Participants |
| Region of Enrollment Canada | 71 participants | 147 participants | 76 participants |
| Region of Enrollment United States | 362 participants | 738 participants | 376 participants |
| Sex: Female, Male Female | 184 Participants | 387 Participants | 203 Participants |
| Sex: Female, Male Male | 249 Participants | 498 Participants | 249 Participants |
| Smoking History (Pack Years) | 50.0 Pack Years STANDARD_DEVIATION 26.1 | 50.6 Pack Years STANDARD_DEVIATION 27.4 | 51.2 Pack Years STANDARD_DEVIATION 28.7 |
| Systemic glucocorticoid or antibiotic use within previous 12 mo No | 66 participants | 136 participants | 70 participants |
| Systemic glucocorticoid or antibiotic use within previous 12 mo Yes | 367 participants | 749 participants | 382 participants |
| Use of supplemental oxygen within previous 12 mo No | 235 participants | 465 participants | 230 participants |
| Use of supplemental oxygen within previous 12 mo Yes | 198 participants | 420 participants | 222 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 316 / 433 | 329 / 452 |
| serious Total, serious adverse events | 178 / 433 | 190 / 452 |
Outcome results
Primary
Rates of COPD Exacerbations
Time frame: up to 37 months
Population: Analysis excludes participants without any follow-up data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Simvastatin | Rates of COPD Exacerbations | 1.36 exacerbations/person-year | Standard Deviation 1.61 |
| Placebo | Rates of COPD Exacerbations | 1.39 exacerbations/person-year | Standard Deviation 1.73 |
p-value: 0.54negative binomial regression
Secondary
Acute Exacerbation COPD Hospitalization Rates (Events/Patient Year)
Time frame: up to 37 months
Population: Analysis excludes participants without any follow-up data.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Simvastatin | Acute Exacerbation COPD Hospitalization Rates (Events/Patient Year) | 0.31 events per patient year |
| Placebo | Acute Exacerbation COPD Hospitalization Rates (Events/Patient Year) | 0.31 events per patient year |
Secondary
Change in FEV1 (% Pred) From Baseline to Last Measure
Time frame: Baseline, last measure at up to 37 months
Population: Analysis excludes participants without any follow-up data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Simvastatin | Change in FEV1 (% Pred) From Baseline to Last Measure | -0.86 percent predicted |
| Placebo | Change in FEV1 (% Pred) From Baseline to Last Measure | -1.81 percent predicted |
p-value: 0.1461t-test, 2 sided
Secondary
Time to First COPD Exacerbation
Time frame: up to 37 months
Population: Analysis excludes participants without any follow-up data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Simvastatin | Time to First COPD Exacerbation | 223 Days to the first exacerbation |
| Placebo | Time to First COPD Exacerbation | 231 Days to the first exacerbation |
p-value: 0.34Log Rank