title: A Study to Investigate the Efficacy and Safety of an Anti-Interleukin-18 Monoclonal Antibody in the Treatment of Type 2 Diabetes Mellitus.
abstract: OBJECTIVE
  Evidence suggests that chronic subclinical inflammation plays an important role in the pathogenesis of type 2 diabetes (T2DM). Circulating levels of interleukin (IL)-18 appear to be associated with a number of micro- and macrovascular comorbidities of obesity and T2DM. This study was designed to investigate whether inhibition of IL-18 had any therapeutic benefit in the treatment of T2DM. Preliminary efficacy, safety and tolerability, pharmacokinetics, and pharmacodynamics of the anti-IL-18 monoclonal antibody, GSK1070806, were assessed.
  
  
  METHODS
  This was a multicentre, randomized, single-blind (sponsor-unblinded), placebo-controlled, parallel-group, phase IIa trial. Obese patients of either sex, aged 18-70 years, with poorly controlled T2DM on metformin monotherapy were recruited. Patients received two doses, of placebo (n = 12), GSK1070806 0.25 mg/kg (n = 13) or GSK1070806 5 mg/kg (n = 12). The primary end-point was the change from baseline in fasting plasma glucose and weighted mean glucose area under the curve (AUC)(0-4 hours) postmixed meal test on Days 29, 57, and 85.
  
  
  RESULTS
  Thirty-seven patients were randomized to one of the three treatment arms. There were no statistically significant effects of GSK1070806 doses on fasting plasma glucose levels, or weighted mean glucose AUC(0-4 hours) compared with placebo.
  
  
  CONCLUSIONS
  GSK1070806 was well tolerated, and inhibition of IL-18 did not lead to any improvements in glucose control. However, because of study limitations, smaller, potentially clinically meaningful effects of IL-18 inhibition cannot be excluded.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01648153.
authors.affiliation: Respiratory R&D, GlaxoSmithKline, Uxbridge, United Kingdom.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: McKie
authors.affiliation: Immunoinflammation Therapy Area Unit, GlaxoSmithKline, Stevenage, United Kingdom.
authors.forename: Juliet L
authors.initials: JL
authors.lastname: Reid
authors.affiliation: Clinical Statistics, GlaxoSmithKline, Stevenage, United Kingdom.
authors.forename: Prafull C
authors.initials: PC
authors.lastname: Mistry
authors.affiliation: Clinical Immunology, Biopharm R&D, GlaxoSmithKline, King of Prussia, Pennsylvania, United States of America.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: DeWall
authors.affiliation: Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, King of Prussia, Pennsylvania, United States of America.
authors.forename: Lee
authors.initials: L
authors.lastname: Abberley
authors.affiliation: GlaxoSmithKline, Clinical development, Cardiovascular and Metabolic Medicines Development Centre, London, United Kingdom.
authors.forename: Philip D
authors.initials: PD
authors.lastname: Ambery
authors.affiliation: Department of Medicine, University Hospital San Cecilio, Granada, Spain.
authors.forename: Blas
authors.initials: B
authors.lastname: Gil-Extremera
mesh_terms: D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000627:therapeutic use*; D001786:Blood Glucose; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000627:therapeutic use; D020382:Interleukin-18 / Q000276:immunology*; D008297:Male; D008687:Metformin / Q000627:therapeutic use; D008875:Middle Aged; D009765:Obesity / Q000097:blood / Q000150:complications*; D016037:Single-Blind Method; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D001786:Blood Glucose; C000608195:GSK1070806; D007004:Hypoglycemic Agents; D020382:Interleukin-18; D008687:Metformin