title: Low-dose otelixizumab anti-CD3 monoclonal antibody DEFEND-1 study: results of the randomized phase III study in recent-onset human type 1 diabetes.
abstract: OBJECTIVE
  Previous studies demonstrated that the anti-CD3 monoclonal antibody otelixizumab, administered at a total dose of 48-64 mg, can slow the loss of C-peptide in recent-onset type 1 diabetes patients, with frequent reactivation of Epstein Barr virus (EBV). The DEFEND-1 (Durable Response Therapy Evaluation for Early or New-Onset Type 1 Diabetes) trial was designed to test whether a lower dose of otelixizumab could preserve C-peptide secretion in new-onset type 1 diabetes patients.
  
  
  METHODS
  A multicenter, randomized, placebo-controlled trial was performed in sites in the U.S., Canada, and Europe. Two hundred eighty-one patients were randomized to treatment with 3.1 mg otelixizumab administered over 8 days or placebo. The primary end point of the study was the change in C-peptide area under the curve (AUC) from a 2-h mixed-meal tolerance test at month 12.
  
  
  RESULTS
  The change in 2-h C-peptide AUC was not different between placebo-treated patients and otelixizumab-treated patients (-0.20 vs. -0.22 nmol/L, P = 0.81). Secondary end points, including HbA1c, glucose variability, and insulin dose, were also not statistically different between the two groups. More patients in the otelixizumab group than in the placebo group experienced adverse events, mostly grade 1 or grade 2. There was no EBV reactivation (viral load >10,000 copies/10(6) peripheral blood mononuclear cells) in the otelixizumab group, in contrast with previously published studies at higher doses of otelixizumab.
  
  
  CONCLUSIONS
  Otelixizumab was well tolerated in patients with recent-onset type 1 diabetes at a total dose of 3.1 mg, but did not achieve preservation of levels of C-peptide or other markers of metabolic control.
authors.affiliation: LMC Diabetes & Endocrinology, Toronto, Ontario, Canada ronnie.aronson@lmc.ca.
authors.forename: Ronnie
authors.initials: R
authors.lastname: Aronson
authors.affiliation: University of Colorado, Denver, CO.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Gottlieb
authors.affiliation: University of Aarhus, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Jens S
authors.initials: JS
authors.lastname: Christiansen
authors.affiliation: Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Donner
authors.affiliation: San Raffaele Hospital Scientific Institute, Vita Salute San Raffaele University, Milan, Italy.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Bosi
authors.affiliation: Emory University, Atlanta Diabetes Associates, Atlanta, GA.
authors.forename: Bruce W
authors.initials: BW
authors.lastname: Bode
authors.affiliation: Università Campus Bio-Medico di Roma, Rome, Italy Barts and the London School of Medicine and Dentistry, Queen Mary, University of London, London, U.K.
authors.forename: Paolo
authors.initials: P
authors.lastname: Pozzilli
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D002096:C-Peptide / Q000097:blood; D017252:CD3 Complex / Q000276:immunology; D002170:Canada / Q000453:epidemiology; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D005060:Europe / Q000453:epidemiology; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage*; D007328:Insulin / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D014481:United States; D055815:Young Adult
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D002096:C-Peptide; D017252:CD3 Complex; D007004:Hypoglycemic Agents; D007328:Insulin; C550701:otelixizumab