title: A Randomized Dose-Escalation Study of the Safety and Anti-Inflammatory Activity of the p38 Mitogen-Activated Protein Kinase Inhibitor Dilmapimod in Severe Trauma Subjects at Risk for Acute Respiratory Distress Syndrome.
abstract: OBJECTIVE
  There are no current pharmacological therapies for the prevention or treatment of acute respiratory distress syndrome. Early dysregulated inflammation likely plays a role in acute respiratory distress syndrome development and possibly acute respiratory distress syndrome outcomes. p38 mitogen-activated protein kinase is central to the regulation of multiple inflammatory mediators implicated in acute organ dysfunction and is the target for a novel class of cytokine-suppressive anti-inflammatory drugs. In preclinical models, p38 inhibitors reduce lung injury following pancreatitis and burn injury.
  
  
  METHODS
  We conducted a phase IIa, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the safety and tolerability of dilmapimod, a novel p38 mitogen-activated protein kinase inhibitor, in patients at risk for developing acute respiratory distress syndrome admitted with an Injury Severity Score more than 16, excluding head trauma. Enrolled patients received 4- or 24-hour IV dilmapimod infusions at different doses or placebo, daily for 3 days, in four separate cohorts.
  
  
  METHODS
  Multicenter randomized clinical trial of large, academic trauma centers.
  
  
  RESULTS
  Seventy-seven patients were enrolled. Although adverse events were common in this critically ill population, dilmapimod was well tolerated, with no clinically relevant safety findings. Pharmacokinetic models indicated that the higher dose of 10 mg given as continuous infusion over 24 hours had the most favorable plasma concentration profile. Likewise, measures of soluble inflammatory markers including interleukin-6, C-reactive peptide, interleukin-8, and soluble tumor necrosis factor receptor 1 were most different between this dosing arm and placebo. Although the study was not specifically designed with acute respiratory distress syndrome as an outcome, the number of patients who developed acute respiratory distress syndrome was small (2/77).
  
  
  CONCLUSIONS
  The novel p38 mitogen-activated protein kinase inhibitor dilmapimod appears well tolerated and may merit further evaluation for prevention of acute respiratory distress syndrome and other organ injury in larger clinical trials. Furthermore, results of this early-phase trial may aid in design of future studies aimed at prevention of acute respiratory distress syndrome and other organ injury.
authors.affiliation: 1Pulmonary and Critical Care Medicine, University of Pennsylvania School of Medicine, Center for Clinical Epidemiology and Biostatistics, Philadelphia, PA. 2Department of Surgery, Duke University Medical Center, Durham, NC. 3Department of Surgery, University of Kentucky, Lexington, KY. 4Division of Trauma and Surgical Critical Care, Vanderbilt University Medical Center, Nashville, TN. 5Department of Critical Care Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA. 6GlaxoSmithKline, Stockley Park, UK. 7GlaxoSmithKline, Stevenage, UK. 8GlaxoSmithKline, King of Prussia, PA.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Christie
authors.forename: Steven
authors.initials: S
authors.lastname: Vaslef
authors.forename: Philip K
authors.initials: PK
authors.lastname: Chang
authors.forename: Addison K
authors.initials: AK
authors.lastname: May
authors.forename: Scott R
authors.initials: SR
authors.lastname: Gunn
authors.forename: Shuying
authors.initials: S
authors.lastname: Yang
authors.forename: Kelly
authors.initials: K
authors.lastname: Hardes
authors.forename: Lesley
authors.initials: L
authors.lastname: Kahl
authors.forename: William M
authors.initials: WM
authors.lastname: Powley
authors.forename: David A
authors.initials: DA
authors.lastname: Lipson
authors.forename: Andrew I
authors.initials: AI
authors.lastname: Bayliffe
authors.forename: Aili L
authors.initials: AL
authors.lastname: Lazaar
mesh_terms: D000328:Adult; D002097:C-Reactive Protein / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D017052:Hospital Mortality; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D015850:Interleukin-6 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D011728:Pyridones / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology*; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000187:drug effects; D012128:Respiratory Distress Syndrome / Q000517:prevention & control*; D015599:Trauma Severity Indices; D014947:Wounds and Injuries / Q000188:drug therapy*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: D018836:Inflammation Mediators; D015850:Interleukin-6; D016209:Interleukin-8; D011728:Pyridones; D011743:Pyrimidines; D047888:Receptors, Tumor Necrosis Factor, Type I; D002097:C-Reactive Protein; D048051:p38 Mitogen-Activated Protein Kinases; C574213:dilmapimod