Simvastatin Therapy for Moderate and Severe COPD (STATCOPE)

Prospective Randomized Placebo-Controlled Trial of SimvaSTATin in the Prevention of COPD Exacerbations (STATCOPE)

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.

Study Overview

• Status: Terminated
• Conditions: Pulmonary Disease, Chronic Obstructive
• Intervention / Treatment: Drug: simvastatin; Drug: Placebo

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

• Study Type: Interventional
• Enrollment (Actual): 885
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Quebec, Canada, G1V 4G5
    • Institut Universitaire de Cardiologie et de Pneumologie de Québec (Laval Hospital)
  • Alberta
    • Calgary, Alberta, Canada, T2N4Z6
      • University of Calgary
    • Edmonton, Alberta, Canada, T6G 2C8
      • University of Alberta
  • British Columbia
    • New Westminster, British Columbia, Canada
      • Royal Columbian Hospital
    • Surrey, British Columbia, Canada, V3V1N1
      • Surrey Memorial Hospital
    • Vancouver, British Columbia, Canada, V6Z 1Y6
      • St. Paul's Hospital
    • Vancouver, British Columbia, Canada, V5Z1M9
      • Vancouver General Hospital
    • Vancouver, British Columbia, Canada, V7M2H9
      • Lion's Gate Hospital
  • Manitoba
    • Winnipeg, Manitoba, Canada, R2H2A6
      • St. Boniface Hospital
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 3A7
      • Queen Elizabeth II Health Sciences Center
  • Ontario
    • Hamilton, Ontario, Canada, L8N 4A6
      • St. Joseph's Healthcare Hamilton
    • Ottawa, Ontario, Canada, K1H 8L6
      • The Ottawa Hospital
    • Ottawa, Ontario, Canada, K1Y4E9
      • Ottawa Civic Hospital
    • Toronto, Ontario, Canada, M5T 3A9
      • Inspiration Research Limited
  • Quebec
    • Montreal, Quebec, Canada, H3T 1E2
      • Jewish General Hospital
  • Saskatchewan
    • Saskatoon, Saskatchewan, Canada, S7N 0W8
      • Royal University Hospital
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama at Birmingham
    • Birmingham, Alabama, United States, 35294
      • Veteran's Administration Medical Center
  • California
    • Los Angeles, California, United States, 90502
      • LA BioMed at Harbor-UCLA Medical Center
    • San Francisco, California, United States, 94143
      • University of California at San Francisco
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University Of Colorado
    • Denver, Colorado, United States, 80206
      • National Jewish Health
  • Florida
    • Gainesville, Florida, United States, 32608
      • Malcom Randall VA Medical Center
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
    • Chicago, Illinois, United States, 60637
      • University of Illinois Health System
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • LSU Health
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland Baltimore
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital
    • Boston, Massachusetts, United States, 02132
      • Veteran's Administration Medical Center
    • Worcester, Massachusetts, United States, 01608
      • Reliant Medical Group
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
    • Ann Arbor, Michigan, United States, 48105
      • Veteran's Administration Medical Center
  • Minnesota
    • Minneapolis, Minnesota, United States, 55440
      • HealthPartners Research Foundation
    • Minneapolis, Minnesota, United States, 55417
      • Veteran's Administration Medical Center
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • New Mexico
    • Albuquerque, New Mexico, United States, 87108
      • Lovelace Respiratory Research Institute
  • New York
    • Buffalo, New York, United States, 14125
      • Western New York Veterans Administration Healthcare System
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University
  • Ohio
    • Cincinnati, Ohio, United States, 45220
      • Cincinnati VAMC
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
    • Columbus, Ohio, United States, 43221
      • Ohio State University
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University
  • Pennsylvania
    • Bethlehem, Pennsylvania, United States, 18015
      • St. Luke's Hospital and Health Network
    • Danville, Pennsylvania, United States, 17822
      • Geisinger Medical Center
    • Langhorne, Pennsylvania, United States, 19047
      • Institute for Respiratory and Sleep
    • Philadelphia, Pennsylvania, United States, 19140
      • Temple University Lung Center
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh
    • Pittsburgh, Pennsylvania, United States, 15240
      • Pittsburgh VA Medical Center
    • Wyomissing, Pennsylvania, United States, 19601
      • Respiratory Specialists
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah Health Sciences Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: simvastatin; 40 mgms of simvastatin daily	Drug: simvastatin; 40 mgms of simvastatin daily; Other Names: Zocor
Placebo Comparator: placebo; Matched placebo pill daily	Drug: Placebo; Matched placebo pill daily; Other Names: sugar pill

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Rates of COPD Exacerbations	up to 37 months

Secondary Outcome Measures

Outcome 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

Collaborators and Investigators

• Sponsor: University of Minnesota
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); Canadian Institutes of Health Research (CIHR); Ottawa Hospital Research Institute
• Investigators: Principal Investigator: John E Connett, PhD, University of Minnesota (Data Coordinating Center); Principal Investigator: Steven M Scharf, MD, PhD, University of Maryland, Baltimore; Principal Investigator: George Washko, MD, Brigham and Women's Hospital Boston; Principal Investigator: Richard K Albert, MD, Denver Health Medical Center; Principal Investigator: Richard Casaburi, MD, PhD, Harbor-UCLA Research & Education Institute; Principal Investigator: Dennis E Niewoehner, MD, Minnesota Veterans Affairs Medical Center; Principal Investigator: Gerard J Criner, MD, Temple University Philadelphia; Principal Investigator: Frank Sciurba, MD, University of Pittsburgh; Principal Investigator: Stephen C Lazarus, MD, University of California at San Francisco; Principal Investigator: Fernando J Martinez, MD, University of Michigan; Principal Investigator: Don Sin, M.D., St. Paul's Hospital; Principal Investigator: Shawn Aaron, M.D., The Ottawa Hospital

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: March 1, 2010
• Primary Completion (Actual): January 1, 2014
• Study Completion (Actual): January 1, 2014

Study Registration Dates

• First Submitted: February 2, 2010
• First Submitted That Met QC Criteria: February 2, 2010
• First Posted (Estimate): February 3, 2010

Study Record Updates

• Last Update Posted (Actual): January 2, 2018
• Last Update Submitted That Met QC Criteria: December 8, 2017
• Last Verified: December 1, 2017

More Information

Terms related to this study

• Keywords: COPD; Smoking; Cardiovascular; Lung function; Chronic Obstructive Pulmonary Disease; Exacerbation; Statins; Simvastatin
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Pulmonary Disease, Chronic Obstructive; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Simvastatin
• Other Study ID Numbers: 689; U10HL074424 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No