title: A Novel Drug for Treatment of Necrotizing Soft-Tissue Infections: A Randomized Clinical Trial.
abstract: OBJECTIVE
  Necrotizing soft-tissue infections (NSTI) have high morbidity and mortality rates despite aggressive surgical debridement and antibiotic therapy. AB103 is a peptide mimetic of the T-lymphocyte receptor, CD28. We hypothesized that AB103 will limit inflammatory responses to bacterial toxins and decrease the incidence of organ failure.
  
  
  OBJECTIVE
  To establish the safety of AB103 in patients with NSTI and evaluate the potential effects on clinically meaningful parameters related to the disease.
  
  
  METHODS
  A prospective, randomized, placebo-controlled, double-blinded study was performed in 6 academic medical centers in the United States. Participants included adults with NSTI. Of 345 patients screened, 43 were enrolled for the intent-to-treat analysis, and 40 met criteria for the modified intent-to-treat analysis; 15 patients each were included in the high-dose and low-dose treatment arms, and 10 in the placebo arm.
  
  
  METHODS
  Single intravenous dose of AB103 (0.5 or 0.25 mg/kg) within 6 hours after diagnosis of NSTI.
  
  
  METHODS
  Change in the Sequential Organ Failure Assessment score within 28 days, intensive care unit-free and ventilator-free days, number and timing of debridements, plasma and tissue cytokine levels at 0 to 72 hours, and adverse events.
  
  
  RESULTS
  Baseline characteristics were comparable in the treatment groups. The Sequential Organ Failure Assessment score improved from baseline in both treatment groups compared with the placebo group at 14 days (change from baseline score, -2.8 in the high-dose, -2 in the low-dose, and +1.3 in the placebo groups; P = .04). AB103-treated patients had a similar number of debridements (mean [SD], 2.2 [1.1] for the high-dose, 2.3 [1.2] for the low-dose, and 2.8 [2.1] for the placebo groups; P = .56). There were no statistically significant differences in intensive care unit-free and ventilator-free days or in plasma and tissue cytokine levels. No drug-related adverse events were detected.
  
  
  CONCLUSIONS
  AB103 is a safe, promising new agent for modulation of inflammation after NSTI. Further study is warranted to establish efficacy.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT01417780.
authors.affiliation: Department of Surgery, Harborview Medical Center, University of Washington, Seattle.
authors.forename: Eileen M
authors.initials: EM
authors.lastname: Bulger
authors.affiliation: Department of Surgery, Harborview Medical Center, University of Washington, Seattle.
authors.forename: Ronald V
authors.initials: RV
authors.lastname: Maier
authors.affiliation: University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Jason
authors.initials: J
authors.lastname: Sperry
authors.affiliation: Department of Surgery and Medicine, University of Maryland, Baltimore.
authors.forename: Manjari
authors.initials: M
authors.lastname: Joshi
authors.affiliation: Department of Surgery and Medicine, University of Maryland, Baltimore.
authors.forename: Sharon
authors.initials: S
authors.lastname: Henry
authors.affiliation: Department of Surgery, University of Florida, Gainesville.
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Moore
authors.affiliation: Department of Surgery, University of Florida, Gainesville.
authors.forename: Lyle L
authors.initials: LL
authors.lastname: Moldawer
authors.affiliation: Department of Surgery, University of Southern California, Los Angeles.
authors.forename: Demetrios
authors.initials: D
authors.lastname: Demetriades
authors.affiliation: Department of Surgery, University of Southern California, Los Angeles.
authors.forename: Peep
authors.initials: P
authors.lastname: Talving
authors.affiliation: Department of Surgery, Oregon Health & Science University, Portland.
authors.forename: Martin
authors.initials: M
authors.lastname: Schreiber
authors.affiliation: Department of Surgery, Oregon Health & Science University, Portland.
authors.forename: Bruce
authors.initials: B
authors.lastname: Ham
authors.affiliation: Department of Surgery, University of California, San Francisco.
authors.forename: Mitchell
authors.initials: M
authors.lastname: Cohen
authors.affiliation: Department of Medicine, Alpert Medical School of Brown University, Providence, Rhode Island.
authors.forename: Steven
authors.initials: S
authors.lastname: Opal
authors.affiliation: Atox Bio Ltd, Ness Ziona, Israel.
authors.forename: Irit
authors.initials: I
authors.lastname: Segalovich
authors.affiliation: Biomedical Statistical Consulting, Wynnewood, Pennsylvania.
authors.forename: Greg
authors.initials: G
authors.lastname: Maislin
authors.affiliation: Atox Bio Ltd, Ness Ziona, Israel11Department of Molecular Biology, Hebrew University Hadassah Medical School, Jerusalem, Israel.
authors.forename: Raymond
authors.initials: R
authors.lastname: Kaempfer
authors.affiliation: Atox Bio Ltd, Ness Ziona, Israel.
authors.forename: Anat
authors.initials: A
authors.lastname: Shirvan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018106:CD28 Antigens / Q000008:administration & dosage / Q000627:therapeutic use*; D016207:Cytokines / Q000032:analysis; D003646:Debridement; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D009336:Necrosis; D063305:Organ Dysfunction Scores; D010919:Placebos; D011446:Prospective Studies; D018461:Soft Tissue Infections / Q000188:drug therapy*; D016896:Treatment Outcome; D014481:United States
chemical_list: D018106:CD28 Antigens; D016207:Cytokines; D010919:Placebos; C000597133:AB103