Larazotide acetate in patients with coeliac disease undergoing a gluten challenge

A randomised placebo-controlled study

C. P. Kelly, P. H.R. Green, J. A. Murray, A. Dimarino, A. Colatrella, D. A. Leffler, T. Alexander, Razvan Arsenescu, F. Leon, J. G. Jiang, L. A. Arterburn, B. M. Paterson, R. N. Fedorak

Research output: Contribution to journalArticle

105 Citations (Scopus)

Abstract

Background Coeliac disease, an autoimmune disorder triggered by gluten ingestion, is managed by a gluten-free diet (GFD), which is difficult for many patients. Larazotide acetate is a first-in-class oral peptide that prevents tight junction opening, and may reduce gluten uptake and associated sequelae. Aim To evaluate the efficacy and tolerability of larazotide acetate during gluten challenge. Methods This exploratory, double-blind, randomised, placebo-controlled study included 184 patients maintaining a GFD before and during the study. After a GFD run-in, patients were randomised to larazotide acetate (1, 4, or 8 mg three times daily) or placebo and received 2.7 grams of gluten daily for 6 weeks. Outcomes included an experimental biomarker of intestinal permeability, the lactulose-to-mannitol (LAMA) ratio and clinical symptoms assessed by Gastrointestinal Symptom Rating Scale (GSRS) and anti-transglutaminase antibody levels. Results No significant differences in LAMA ratios were observed between larazotide acetate and placebo groups. Larazotide acetate 1-mg limited gluten-induced symptoms measured by GSRS (P = 0.002 vs. placebo). Mean ratio of anti-tissue transglutaminase IgA levels over baseline was 19.0 in the placebo group compared with 5.78 (P = 0.010), 3.88 (P = 0.005) and 7.72 (P = 0.025) in the larazotide acetate 1-, 4-, and 8-mg groups, respectively. Adverse event rates were similar between larazotide acetate and placebo groups. Conclusions Larazotide acetate reduced gluten-induced immune reactivity and symptoms in patients with coeliac disease undergoing gluten challenge and was generally well tolerated; however, no significant difference in LAMA ratios between larazotide acetate and placebo was observed. Results and design of this exploratory study can inform the design of future studies of pharmacological interventions in patients with coeliac disease.

Original languageEnglish (US)
Pages (from-to)252-262
Number of pages11
JournalAlimentary Pharmacology and Therapeutics
Volume37
Issue number2
DOIs
StatePublished - Jan 1 2013

Fingerprint

Glutens
Celiac Disease
Placebos
Lactulose
Gluten-Free Diet
Mannitol
AT-1001
Transglutaminases
Tight Junctions
Immunoglobulin A
Anti-Idiotypic Antibodies
Permeability
Eating
Biomarkers
Pharmacology
Peptides

All Science Journal Classification (ASJC) codes

  • Hepatology
  • Gastroenterology
  • Pharmacology (medical)

Cite this

Kelly, C. P., Green, P. H. R., Murray, J. A., Dimarino, A., Colatrella, A., Leffler, D. A., ... Fedorak, R. N. (2013). Larazotide acetate in patients with coeliac disease undergoing a gluten challenge: A randomised placebo-controlled study. Alimentary Pharmacology and Therapeutics, 37(2), 252-262. https://doi.org/10.1111/apt.12147
Kelly, C. P. ; Green, P. H.R. ; Murray, J. A. ; Dimarino, A. ; Colatrella, A. ; Leffler, D. A. ; Alexander, T. ; Arsenescu, Razvan ; Leon, F. ; Jiang, J. G. ; Arterburn, L. A. ; Paterson, B. M. ; Fedorak, R. N. / Larazotide acetate in patients with coeliac disease undergoing a gluten challenge : A randomised placebo-controlled study. In: Alimentary Pharmacology and Therapeutics. 2013 ; Vol. 37, No. 2. pp. 252-262.
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abstract = "Background Coeliac disease, an autoimmune disorder triggered by gluten ingestion, is managed by a gluten-free diet (GFD), which is difficult for many patients. Larazotide acetate is a first-in-class oral peptide that prevents tight junction opening, and may reduce gluten uptake and associated sequelae. Aim To evaluate the efficacy and tolerability of larazotide acetate during gluten challenge. Methods This exploratory, double-blind, randomised, placebo-controlled study included 184 patients maintaining a GFD before and during the study. After a GFD run-in, patients were randomised to larazotide acetate (1, 4, or 8 mg three times daily) or placebo and received 2.7 grams of gluten daily for 6 weeks. Outcomes included an experimental biomarker of intestinal permeability, the lactulose-to-mannitol (LAMA) ratio and clinical symptoms assessed by Gastrointestinal Symptom Rating Scale (GSRS) and anti-transglutaminase antibody levels. Results No significant differences in LAMA ratios were observed between larazotide acetate and placebo groups. Larazotide acetate 1-mg limited gluten-induced symptoms measured by GSRS (P = 0.002 vs. placebo). Mean ratio of anti-tissue transglutaminase IgA levels over baseline was 19.0 in the placebo group compared with 5.78 (P = 0.010), 3.88 (P = 0.005) and 7.72 (P = 0.025) in the larazotide acetate 1-, 4-, and 8-mg groups, respectively. Adverse event rates were similar between larazotide acetate and placebo groups. Conclusions Larazotide acetate reduced gluten-induced immune reactivity and symptoms in patients with coeliac disease undergoing gluten challenge and was generally well tolerated; however, no significant difference in LAMA ratios between larazotide acetate and placebo was observed. Results and design of this exploratory study can inform the design of future studies of pharmacological interventions in patients with coeliac disease.",
author = "Kelly, {C. P.} and Green, {P. H.R.} and Murray, {J. A.} and A. Dimarino and A. Colatrella and Leffler, {D. A.} and T. Alexander and Razvan Arsenescu and F. Leon and Jiang, {J. G.} and Arterburn, {L. A.} and Paterson, {B. M.} and Fedorak, {R. N.}",
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Kelly, CP, Green, PHR, Murray, JA, Dimarino, A, Colatrella, A, Leffler, DA, Alexander, T, Arsenescu, R, Leon, F, Jiang, JG, Arterburn, LA, Paterson, BM & Fedorak, RN 2013, 'Larazotide acetate in patients with coeliac disease undergoing a gluten challenge: A randomised placebo-controlled study', Alimentary Pharmacology and Therapeutics, vol. 37, no. 2, pp. 252-262. https://doi.org/10.1111/apt.12147

Larazotide acetate in patients with coeliac disease undergoing a gluten challenge : A randomised placebo-controlled study. / Kelly, C. P.; Green, P. H.R.; Murray, J. A.; Dimarino, A.; Colatrella, A.; Leffler, D. A.; Alexander, T.; Arsenescu, Razvan; Leon, F.; Jiang, J. G.; Arterburn, L. A.; Paterson, B. M.; Fedorak, R. N.

In: Alimentary Pharmacology and Therapeutics, Vol. 37, No. 2, 01.01.2013, p. 252-262.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Larazotide acetate in patients with coeliac disease undergoing a gluten challenge

T2 - A randomised placebo-controlled study

AU - Kelly, C. P.

AU - Green, P. H.R.

AU - Murray, J. A.

AU - Dimarino, A.

AU - Colatrella, A.

AU - Leffler, D. A.

AU - Alexander, T.

AU - Arsenescu, Razvan

AU - Leon, F.

AU - Jiang, J. G.

AU - Arterburn, L. A.

AU - Paterson, B. M.

AU - Fedorak, R. N.

PY - 2013/1/1

Y1 - 2013/1/1

N2 - Background Coeliac disease, an autoimmune disorder triggered by gluten ingestion, is managed by a gluten-free diet (GFD), which is difficult for many patients. Larazotide acetate is a first-in-class oral peptide that prevents tight junction opening, and may reduce gluten uptake and associated sequelae. Aim To evaluate the efficacy and tolerability of larazotide acetate during gluten challenge. Methods This exploratory, double-blind, randomised, placebo-controlled study included 184 patients maintaining a GFD before and during the study. After a GFD run-in, patients were randomised to larazotide acetate (1, 4, or 8 mg three times daily) or placebo and received 2.7 grams of gluten daily for 6 weeks. Outcomes included an experimental biomarker of intestinal permeability, the lactulose-to-mannitol (LAMA) ratio and clinical symptoms assessed by Gastrointestinal Symptom Rating Scale (GSRS) and anti-transglutaminase antibody levels. Results No significant differences in LAMA ratios were observed between larazotide acetate and placebo groups. Larazotide acetate 1-mg limited gluten-induced symptoms measured by GSRS (P = 0.002 vs. placebo). Mean ratio of anti-tissue transglutaminase IgA levels over baseline was 19.0 in the placebo group compared with 5.78 (P = 0.010), 3.88 (P = 0.005) and 7.72 (P = 0.025) in the larazotide acetate 1-, 4-, and 8-mg groups, respectively. Adverse event rates were similar between larazotide acetate and placebo groups. Conclusions Larazotide acetate reduced gluten-induced immune reactivity and symptoms in patients with coeliac disease undergoing gluten challenge and was generally well tolerated; however, no significant difference in LAMA ratios between larazotide acetate and placebo was observed. Results and design of this exploratory study can inform the design of future studies of pharmacological interventions in patients with coeliac disease.

AB - Background Coeliac disease, an autoimmune disorder triggered by gluten ingestion, is managed by a gluten-free diet (GFD), which is difficult for many patients. Larazotide acetate is a first-in-class oral peptide that prevents tight junction opening, and may reduce gluten uptake and associated sequelae. Aim To evaluate the efficacy and tolerability of larazotide acetate during gluten challenge. Methods This exploratory, double-blind, randomised, placebo-controlled study included 184 patients maintaining a GFD before and during the study. After a GFD run-in, patients were randomised to larazotide acetate (1, 4, or 8 mg three times daily) or placebo and received 2.7 grams of gluten daily for 6 weeks. Outcomes included an experimental biomarker of intestinal permeability, the lactulose-to-mannitol (LAMA) ratio and clinical symptoms assessed by Gastrointestinal Symptom Rating Scale (GSRS) and anti-transglutaminase antibody levels. Results No significant differences in LAMA ratios were observed between larazotide acetate and placebo groups. Larazotide acetate 1-mg limited gluten-induced symptoms measured by GSRS (P = 0.002 vs. placebo). Mean ratio of anti-tissue transglutaminase IgA levels over baseline was 19.0 in the placebo group compared with 5.78 (P = 0.010), 3.88 (P = 0.005) and 7.72 (P = 0.025) in the larazotide acetate 1-, 4-, and 8-mg groups, respectively. Adverse event rates were similar between larazotide acetate and placebo groups. Conclusions Larazotide acetate reduced gluten-induced immune reactivity and symptoms in patients with coeliac disease undergoing gluten challenge and was generally well tolerated; however, no significant difference in LAMA ratios between larazotide acetate and placebo was observed. Results and design of this exploratory study can inform the design of future studies of pharmacological interventions in patients with coeliac disease.

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U2 - 10.1111/apt.12147

DO - 10.1111/apt.12147

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