title: A randomized, double-blind study of larazotide acetate to prevent the activation of celiac disease during gluten challenge.
abstract: OBJECTIVE
  In patients with celiac disease, enteropathy is caused by the entry of gluten peptides into the lamina propria of the intestine, in which their immunogenicity is potentiated by tissue transglutaminase (tTG) and T-helper type 1-mediated immune responses are triggered. Tight junction disassembly and paracellular permeability are believed to have an important role in the transport of gluten peptides to the lamina propria. Larazotide acetate is a tight-junction regulator peptide that, in vitro, prevents the opening of intestinal epithelial tight junctions. The aim of this study was to evaluate the efficacy and tolerability of larazotide acetate in protecting against gluten-induced intestinal permeability and gastrointestinal symptom severity in patients with celiac disease.
  
  
  METHODS
  In this dose-ranging, placebo-controlled study, 86 patients with celiac disease controlled through diet were randomly assigned to larazotide acetate (0.25, 1, 4, or 8 mg) or placebo three times per day with or without gluten challenge (2.4 g/day) for 14 days. The primary efficacy outcome was the urinary lactulose/mannitol (LAMA) fractional excretion ratio. Secondary endpoints included gastrointestinal symptom severity, quality-of-life measures, and antibodies to tTG.
  
  
  RESULTS
  LAMA measurements were highly variable in the outpatient setting. The increase in LAMA ratio associated with the gluten challenge was not statistically significantly greater than the increase in the gluten-free control. Among patients receiving the gluten challenge, the difference in the LAMA ratios for the larazotide acetate and placebo groups was not statistically significant. However, larazotide acetate appeared to limit gluten-induced worsening of gastrointestinal symptom severity as measured by the Gastrointestinal Symptom Rating Scale at some lower doses but not at the higher dose. Symptoms worsened significantly in the gluten challenge-placebo arm compared with the placebo-placebo arm, suggesting that 2.4 g of gluten per day is sufficient to induce reproducible gluten toxicity. Larazotide acetate was generally well tolerated. No serious adverse events were observed. The most common adverse events were headache and urinary tract infection.
  
  
  CONCLUSIONS
  LAMA variability in the outpatient setting precluded accurate assessment of the effect of larazotide acetate on intestinal permeability. However, some lower doses of larazotide acetate appeared to prevent the increase in gastrointestinal symptom severity induced by gluten challenge.
authors: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. dleffler@caregroup.harvard.edu
authors: Daniel A
authors: DA
authors: Leffler
authors: C P
authors: CP
authors: Kelly
authors: H Z
authors: HZ
authors: Abdallah
authors: A M
authors: AM
authors: Colatrella
authors: L A
authors: LA
authors: Harris
authors: F
authors: F
authors: Leon
authors: L A
authors: LA
authors: Arterburn
authors: B M
authors: BM
authors: Paterson
authors: Z H
authors: ZH
authors: Lan
authors: J A
authors: JA
authors: Murray
mesh_terms: D000208:Acute Disease; D000328:Adult; D002446:Celiac Disease / Q000517:prevention & control*; D004311:Double-Blind Method; D005260:Female; D005765:Gastrointestinal Agents / Q000627:therapeutic use*; D005983:Glutens / Q000008:administration & dosage*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000627:therapeutic use*; D055502:Secondary Prevention / Q000379:methods; D012720:Severity of Illness Index; D019108:Tight Junctions / Q000187:drug effects
chemical_list: D005765:Gastrointestinal Agents; D009842:Oligopeptides; D005983:Glutens; C525167:larazotide acetate