Clinical trial NCT01061671: Simvastatin Therapy for Moderate and Severe COPD
Official title: Prospective Randomized Placebo-Controlled Trial of SimvaSTATin in the Prevention of COPD Exacerbations (STATCOPE)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Pulmonary Disease, Chronic Obstructive
Keywords: Chronic Obstructive Pulmonary Disease
COPD
Exacerbation
Lung function
Cardiovascular
Smoking
Statins
Simvastatin
Lead sponsor: University of Minnesota
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
name: Canadian Institutes of Health Research (CIHR)
name: Ottawa Hospital Research Institute
First posted: 2010-02-03
Enrollment: 885
Sex: ALL
Minimum age (years): 40
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

Eligibility criteria: 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.

Primary outcomes:
measure: Rates of COPD Exacerbations
timeFrame: up to 37 months
Secondary outcomes:
measure: Time to First COPD Exacerbation
timeFrame: up to 37 months
measure: Change in FEV1 (% Pred) From Baseline to Last Measure
timeFrame: Baseline, last measure at up to 37 months
measure: Acute Exacerbation COPD Hospitalization Rates (Events/Patient Year)
timeFrame: up to 37 months
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Birmingham
country: United States
facility: Veteran's Administration Medical Center
state: Alabama
city: Los Angeles
country: United States
facility: LA BioMed at Harbor-UCLA Medical Center
state: California
city: San Francisco
country: United States
facility: University of California at San Francisco
state: California
city: Aurora
country: United States
facility: University of Colorado
state: Colorado
city: Denver
country: United States
facility: National Jewish Health
state: Colorado
city: Gainesville
country: United States
facility: Malcom Randall VA Medical Center
state: Florida
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: University of Illinois Health System
state: Illinois
city: New Orleans
country: United States
facility: LSU Health
state: Louisiana
city: Baltimore
country: United States
facility: University of Maryland Baltimore
state: Maryland
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Boston
country: United States
facility: Veteran's Administration Medical Center
state: Massachusetts
city: Worcester
country: United States
facility: Reliant Medical Group
state: Massachusetts
city: Ann Arbor
country: United States
facility: Veteran's Administration Medical Center
state: Michigan
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Minneapolis
country: United States
facility: Veteran's Administration Medical Center
state: Minnesota
city: Minneapolis
country: United States
facility: HealthPartners Research Foundation
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Albuquerque
country: United States
facility: Lovelace Respiratory Research Institute
state: New Mexico
city: Buffalo
country: United States
facility: Western New York Veterans Administration Healthcare System
state: New York
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati VAMC
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Bethlehem
country: United States
facility: St. Luke's Hospital and Health Network
state: Pennsylvania
city: Danville
country: United States
facility: Geisinger Medical Center
state: Pennsylvania
city: Langhorne
country: United States
facility: Institute for Respiratory and Sleep
state: Pennsylvania
city: Philadelphia
country: United States
facility: Temple University Lung Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Pittsburgh VA Medical Center
state: Pennsylvania
city: Wyomissing
country: United States
facility: Respiratory Specialists
state: Pennsylvania
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah Health Sciences Center
state: Utah
city: Calgary
country: Canada
facility: University of Calgary
state: Alberta
city: Edmonton
country: Canada
facility: University of Alberta
state: Alberta
city: New Westminster
country: Canada
facility: Royal Columbian Hospital
state: British Columbia
city: Surrey
country: Canada
facility: Surrey Memorial Hospital
state: British Columbia
city: Vancouver
country: Canada
facility: Vancouver General Hospital
state: British Columbia
city: Vancouver
country: Canada
facility: St. Paul's Hospital
state: British Columbia
city: Vancouver
country: Canada
facility: Lion's Gate Hospital
state: British Columbia
city: Winnipeg
country: Canada
facility: St. Boniface Hospital
state: Manitoba
city: Halifax
country: Canada
facility: Queen Elizabeth II Health Sciences Center
state: Nova Scotia
city: Hamilton
country: Canada
facility: St. Joseph's Healthcare Hamilton
state: Ontario
city: Ottawa
country: Canada
facility: The Ottawa Hospital
state: Ontario
city: Ottawa
country: Canada
facility: Ottawa Civic Hospital
state: Ontario
city: Toronto
country: Canada
facility: Inspiration Research Limited
state: Ontario
city: Montreal
country: Canada
facility: Jewish General Hospital
state: Quebec
city: Saskatoon
country: Canada
facility: Royal University Hospital
state: Saskatchewan
city: Quebec
country: Canada
facility: Institut Universitaire de Cardiologie et de Pneumologie de Québec (Laval Hospital)
Study officials:
affiliation: University of Minnesota (Data Coordinating Center)
name: John E Connett, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Maryland, Baltimore
name: Steven M Scharf, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Alabama at Birmingham
name: Mark Dransfield, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Brigham and Women's Hospital Boston
name: George Washko, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Denver Health Medical Center
name: Richard K Albert, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Harbor-UCLA Research & Education Institute
name: Richard Casaburi, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Minnesota Veterans Affairs Medical Center
name: Dennis E Niewoehner, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Temple University Philadelphia
name: Gerard J Criner, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Pittsburgh
name: Frank Sciurba, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California at San Francisco
name: Stephen C Lazarus, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Michigan
name: Fernando J Martinez, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: St. Paul's Hospital
name: Don Sin, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: The Ottawa Hospital
name: Shawn Aaron, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Camac ER, Voelker H, Criner GJ; COPD Clinical Research Network and the Canadian Institutes of Health Research. Impact of COPD exacerbations leading to hospitalization on general and disease-specific quality of life. Respir Med. 2021 Sep;186:106526. doi: 10.1016/j.rmed.2021.106526. Epub 2021 Jun 29.
citation: Rao AK, Del Carpio-Cano F, Janapati S, Zhao H, Voelker H, Lu X, Criner G; NIH COPD Clinical Research Network, the Canadian Institute of Health Research Investigators. Effects of simvastatin on tissue factor pathway of blood coagulation in STATCOPE (Simvastatin in the prevention of COPD exacerbations) trial. J Thromb Haemost. 2021 Jul;19(7):1709-1717. doi: 10.1111/jth.15282. Epub 2021 Apr 12.
citation: Leitao Filho FS, Ra SW, Mattman A, Schellenberg RS, Criner GJ, Woodruff PG, Lazarus SC, Albert R, Connett JE, Han MK, Martinez FJ, Leung JM, Paul Man SF, Aaron SD, Reed RM, Sin DD; Canadian Respiratory Research Network (CRRN). Serum IgG subclass levels and risk of exacerbations and hospitalizations in patients with COPD. Respir Res. 2018 Feb 14;19(1):30. doi: 10.1186/s12931-018-0733-z.
citation: Brown KE, Sin DD, Voelker H, Connett JE, Niewoehner DE, Kunisaki KM; COPD Clinical Research Network. Serum bilirubin and the risk of chronic obstructive pulmonary disease exacerbations. Respir Res. 2017 Oct 24;18(1):179. doi: 10.1186/s12931-017-0664-0.
citation: Criner GJ, Connett JE, Aaron SD, Albert RK, Bailey WC, Casaburi R, Cooper JA Jr, Curtis JL, Dransfield MT, Han MK, Make B, Marchetti N, Martinez FJ, Niewoehner DE, Scanlon PD, Sciurba FC, Scharf SM, Sin DD, Voelker H, Washko GR, Woodruff PG, Lazarus SC; COPD Clinical Research Network; Canadian Institutes of Health Research. Simvastatin for the prevention of exacerbations in moderate-to-severe COPD. N Engl J Med. 2014 Jun 5;370(23):2201-10. doi: 10.1056/NEJMoa1403086. Epub 2014 May 18.