Statins for the Early Treatment of Sepsis - Full Text View

Sponsored by:	University of Chicago
Information provided by:	University of Chicago
ClinicalTrials.gov Identifier:	NCT00528580

Purpose

We propose a Phase II, randomized, placebo-controlled clinical trial to test the hypothesis that treatment with once-daily statins has a beneficial effect on inflammatory cytokines and clinical outcomes in adults hospitalized with sepsis. As our animal models suggest pretreatment with statins are required for their beneficial effects, we propose a study design intended to identify patients and initiate treatment early in their hospital stay. This Phase II study is intended to assess the feasibility of conducting a large-scale investigator-initiated translational research protocol that involves multiple clinical services within the Department of Medicine.

Condition	Intervention	Phase
Sepsis	Drug: Simvastatin Drug: Identical-appearing placebo	Phase II

MedlinePlus related topics: Sepsis Statins

Drug Information available for: Simvastatin

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Parallel Assignment, Safety/Efficacy Study
Official Title:	Statins for the Early Treatment of Sepsis

Further study details as provided by University of Chicago:

Primary Outcome Measures:

Time to clinical stability [ Time Frame: 24 hours ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

Admission to the intensive care unit [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
Use of mechanical ventilation (yes or no) [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
Use of vasopressors for blood pressure support [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
Length of hospital stay [ Time Frame: 28 days ] [ Designated as safety issue: No ]
Hospital-free days to day 28 [ Time Frame: 28 days ] [ Designated as safety issue: No ]
ICU-free days to Day 28 [ Time Frame: 28 days ] [ Designated as safety issue: No ]
Antibiotic-free days to day 28 [ Time Frame: 28 days ] [ Designated as safety issue: No ]
Death or discharge to hospice [ Time Frame: 28 days ] [ Designated as safety issue: No ]
Total ICU costs [ Time Frame: 28 days ] [ Designated as safety issue: No ]
Total hospital costs [ Time Frame: 28 days ] [ Designated as safety issue: No ]
Signs or symptoms of liver toxicity, myositis, elevations in LFTs or CPK, rhabdomyolysis. [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]

Estimated Enrollment:	250
Study Start Date:	February 2008
Estimated Study Completion Date:	March 2010
Estimated Primary Completion Date:	October 2009 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
1: Experimental Simvastatin 80 mg once daily PO (or via NG or G-tube)	Drug: Simvastatin 80 mg once daily PO/NG x 4 days
2: Placebo Comparator Identical-appearing placebo PO (or via NG or G-tube)	Drug: Identical-appearing placebo once daily x 4 days

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Age > 18 years
Initial presentation to the Emergency Department or University of Chicago MD office/Dialysis Center for current hospital admission
Sepsis (ACCP/SCCM criteria)
1. Clinically suspected infection as per the treating physician or confirmed infection
2. 2 or more of the following: Temperature 38ºC (100.4ºF)or 36ºC (96.8ºF), Heart rate (HR) > 90/min, Respiratory rate (RR) > 20/min or PaCO2 < 32 mmHg, White blood cell count > 12,000/mm3 or < 4000/m3 or > 10%immature neutrophils
Initiation of antibiotics by treating physician for sepsis
Hospitalized from the Emergency Department or University of Chicago MD office/Dialysis Center to an inpatient medical service (intensive care unit (ICU)or non-ICU service) OR admission to the medical ICU (MICU) from a non-ICU inpatient medical floor.
Assent of the primary treating physician at the time of enrollment.
The meeting of SIRS criteria is due to an infection as per the treating physician.

Exclusion Criteria:

Pregnancy
ALT >3 times above the upper limit of normal
Elevated creatine phosphokinase (CPK) (>3 times the upper limit of normal)
Concurrent treatment with any of the following drugs: daptomycin, fenofibrate, ketoconazole,triaconazole, amiodarone, clarithromycin, cyclosporine, erythromycin,nefazodone, niacin, protease inhibitors, telithromycin, verapamil,danazol, gemfibrozil
History of allergy or intolerance to statins
Greater than 16 hours after meeting inclusion criteria
Use of 1 more doses of statins in the previous 4 weeks
Clinical indication for treatment with statin during hospital admission (per treating physician)
Sufficiently poor prognosis prior to enrollment that treating physicians have elected to employ comfort care or plan to discharge to hospice
Transfer from surgical service to medical service
Needing transfusion for active bleeding

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00528580

Contacts

Contact: Julie A Johnson, BSN, MPH

773-702-1858

jjohnso3@medicine.bsd.uchicago.edu

Locations

United States, Illinois
The University of Chicago	Recruiting
Chicago, Illinois, United States, 60637
Contact: Jeffrey Jacobson, MD 773-834-2389 jjacobso@medicine.bsd.uchicago.edu
Principal Investigator: Jeffrey Jacobson, MD
Sub-Investigator: Jerry Krishnan, MD, PhD
Sub-Investigator: Skip Garcia, MD

Sponsors and Collaborators

University of Chicago

Investigators

Principal Investigator:

Jeffrey Jacobson, MD

University of Chicago

More Information

Publications:

Oba Y, Salzman GA. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury. N Engl J Med. 2000 Sep 14;343(11):813; author reply 813-4. No abstract available.

Almog Y, Shefer A, Novack V, Maimon N, Barski L, Eizinger M, Friger M, Zeller L, Danon A. Prior statin therapy is associated with a decreased rate of severe sepsis. Circulation. 2004 Aug 17;110(7):880-5. Epub 2004 Aug 2.

[No authors listed] American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med. 1992 Jun;20(6):864-74. Review.

Dunbar LM, Wunderink RG, Habib MP, Smith LG, Tennenberg AM, Khashab MM, Wiesinger BA, Xiang JX, Zadeikis N, Kahn JB. High-dose, short-course levofloxacin for community-acquired pneumonia: a new treatment paradigm. Clin Infect Dis. 2003 Sep 15;37(6):752-60. Epub 2003 Aug 28. Erratum in: Clin Infect Dis. 2003 Oct 15;37(8):1147.

Greenwood J, Walters CE, Pryce G, Kanuga N, Beraud E, Baker D, Adamson P. Lovastatin inhibits brain endothelial cell Rho-mediated lymphocyte migration and attenuates experimental autoimmune encephalomyelitis. FASEB J. 2003 May;17(8):905-7. Epub 2003 Mar 5.

Gupta R, Plantinga LC, Fink NE, Melamed ML, Coresh J, Fox CS, Levin NW, Powe NR. Statin use and hospitalization for sepsis in patients with chronic kidney disease. JAMA. 2007 Apr 4;297(13):1455-64.

Hackam DG, Mamdani M, Li P, Redelmeier DA. Statins and sepsis in patients with cardiovascular disease: a population-based cohort analysis. Lancet. 2006 Feb 4;367(9508):413-8.

Jacobson JR, Barnard JW, Grigoryev DN, Ma SF, Tuder RM, Garcia JG. Simvastatin attenuates vascular leak and inflammation in murine inflammatory lung injury. Am J Physiol Lung Cell Mol Physiol. 2005 Jun;288(6):L1026-32. Epub 2005 Jan 21.

Leung BP, Sattar N, Crilly A, Prach M, McCarey DW, Payne H, Madhok R, Campbell C, Gracie JA, Liew FY, McInnes IB. A novel anti-inflammatory role for simvastatin in inflammatory arthritis. J Immunol. 2003 Feb 1;170(3):1524-30.

Liappis AP, Kan VL, Rochester CG, Simon GL. The effect of statins on mortality in patients with bacteremia. Clin Infect Dis. 2001 Oct 15;33(8):1352-7. Epub 2001 Sep 20.

Majumdar SR, McAlister FA, Eurich DT, Padwal RS, Marrie TJ. Statins and outcomes in patients admitted to hospital with community acquired pneumonia: population based prospective cohort study. BMJ. 2006 Nov 11;333(7576):999. Epub 2006 Oct 23.

Merx MW, Liehn EA, Graf J, van de Sandt A, Schaltenbrand M, Schrader J, Hanrath P, Weber C. Statin treatment after onset of sepsis in a murine model improves survival. Circulation. 2005 Jul 5;112(1):117-24.

Naidu BV, Woolley SM, Farivar AS, Thomas R, Fraga C, Mulligan MS. Simvastatin ameliorates injury in an experimental model of lung ischemia-reperfusion. J Thorac Cardiovasc Surg. 2003 Aug;126(2):482-9.

Schmidt H, Hennen R, Keller A, Russ M, Muller-Werdan U, Werdan K, Buerke M. Association of statin therapy and increased survival in patients with multiple organ dysfunction syndrome. Intensive Care Med. 2006 Aug;32(8):1248-51. Epub 2006 Jun 21.

Thomsen RW, Hundborg HH, Johnsen SP, Pedersen L, Sorensen HT, Schonheyder HC, Lervang HH. Statin use and mortality within 180 days after bacteremia: a population-based cohort study. Crit Care Med. 2006 Apr;34(4):1080-6.

Yasuda H, Yuen PS, Hu X, Zhou H, Star RA. Simvastatin improves sepsis-induced mortality and acute kidney injury via renal vascular effects. Kidney Int. 2006 May;69(9):1535-42.

Responsible Party:	University of Chicago ( Jeffrey Jacobson )
Study ID Numbers:	15420A
Study First Received:	September 11, 2007
Last Updated:	December 22, 2008
ClinicalTrials.gov Identifier:	NCT00528580
Health Authority:	United States: Institutional Review Board

Keywords provided by University of Chicago:

Sepsis
Statin
Infection
Immunomodulatory

Study placed in the following topic categories:

Systemic Inflammatory Response Syndrome
Sepsis
Simvastatin
Inflammation

Additional relevant MeSH terms:

Antimetabolites
Pathologic Processes
Molecular Mechanisms of Pharmacological Action
Therapeutic Uses
Antilipemic Agents

Enzyme Inhibitors
Anticholesteremic Agents
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Infection
Pharmacologic Actions

ClinicalTrials.gov processed this record on January 15, 2009