Statins for the Early Treatment of Sepsis

NCT00528580 | Terminated Phase 2 Results DMC FDA Drug

• 1 other identifier: 15420A
• Study Type: interventional
• Target: 68
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Sepsis

Keywords

Sepsis; Statin; Infection; Immunomodulatory

Outcome Measures

Primary Outcomes (1)

• Time to Clinical Stability

  Normalization of vital signs for each subject enrolled. This is expressed as a mean time to normalization for each +/- standard error.

  24 hours

Study Arms (2)

1

EXPERIMENTAL

Simvastatin 80 mg once daily PO (or via NG or G-tube)

Drug: Simvastatin

2

PLACEBO COMPARATOR

Identical-appearing placebo PO (or via NG or G-tube)

Drug: Identical-appearing placebo

Interventions

Simvastatin DRUG

80 mg once daily PO/NG x 4 days

1

Identical-appearing placebo DRUG

once daily x 4 days

2

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)
• Clinically suspected infection as per the treating physician or confirmed infection
• 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.

You may not qualify if:

• 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
• 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 either active bleeding or severe hemolysis.

Sponsors & Collaborators

• University of Chicago: lead

Study Sites (1)

The University of Chicago

Chicago, Illinois, 60637, United States

Location

Related Publications (17)

• 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.

  PMID: 10991706 BACKGROUND

• 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. doi: 10.1161/01.CIR.0000138932.17956.F1. Epub 2004 Aug 2.

  PMID: 15289367 BACKGROUND

• 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.

  PMID: 1597042 BACKGROUND

• 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. doi: 10.1086/377539. Epub 2003 Aug 28.

  PMID: 12955634 BACKGROUND

• 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. doi: 10.1096/fj.02-1014fje. Epub 2003 Mar 5.

  PMID: 12626426 BACKGROUND

• Gupta R, Plantinga LC, Fink NE, Melamed ML, Coresh J, Fox CS, Levin NW, Powe NR. Statin use and sepsis events [corrected] in patients with chronic kidney disease. JAMA. 2007 Apr 4;297(13):1455-64. doi: 10.1001/jama.297.13.1455.

  PMID: 17405971 BACKGROUND

• 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. doi: 10.1016/S0140-6736(06)68041-0.

  PMID: 16458766 BACKGROUND

• 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. doi: 10.1152/ajplung.00354.2004. Epub 2005 Jan 21.

  PMID: 15665042 BACKGROUND

• 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. doi: 10.4049/jimmunol.170.3.1524.

  PMID: 12538717 BACKGROUND

• 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. doi: 10.1086/323334. Epub 2001 Sep 20.

  PMID: 11565076 BACKGROUND

• 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. doi: 10.1136/bmj.38992.565972.7C. Epub 2006 Oct 23.

  PMID: 17060337 BACKGROUND

• 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. doi: 10.1161/CIRCULATIONAHA.104.502195.

  PMID: 15998696 BACKGROUND

• 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. doi: 10.1016/s0022-5223(03)00699-8.

  PMID: 12928648 BACKGROUND

• 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. doi: 10.1007/s00134-006-0246-y. Epub 2006 Jun 21.

  PMID: 16788803 BACKGROUND

• 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. doi: 10.1097/01.CCM.0000207345.92928.E4.

  PMID: 16484926 BACKGROUND

• 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. doi: 10.1038/sj.ki.5000300.

  PMID: 16557230 BACKGROUND

• Dobesh PP, Olsen KM. Statins role in the prevention and treatment of sepsis. Pharmacol Res. 2014 Oct;88:31-40. doi: 10.1016/j.phrs.2014.04.010. Epub 2014 May 2.

  PMID: 24794878 DERIVED

MeSH Terms

Conditions

Sepsis; Infections

Interventions

Simvastatin

Condition Hierarchy (Ancestors)

Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Lovastatin; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds

Results Point of Contact

• Title: Millie Maleckar
• Organization: University of Chicago

mmalecka@bsd.uchicago.edu

773-702-1472

Study Officials

• Jerry Krishnan, MD

  University of Chicago

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 11, 2007
• First Posted: September 12, 2007
• Study Start: February 1, 2008
• Primary Completion: September 1, 2011
• Study Completion: September 1, 2011
• Last Updated: September 5, 2018
• Results First Posted: June 7, 2018

Record last verified: 2018-08

Locations

US (1)