A randomized, double-blind study of larazotide acetate to prevent the activation of celiac disease during gluten challenge

Daniel A Leffler, C P Kelly, H Z Abdallah, A M Colatrella, L A Harris, F Leon, L A Arterburn, B M Paterson, Z H Lan, J A Murray, Daniel A Leffler, C P Kelly, H Z Abdallah, A M Colatrella, L A Harris, F Leon, L A Arterburn, B M Paterson, Z H Lan, J A Murray

Abstract

Objectives: 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.

Figures

Figure 1
Figure 1
Schema of overall study design and participant allocation. (a) Study design and (b) disposition of patients. LAMA, lactulose/mannitol.
Figure 2
Figure 2
Change from baseline LAMA levels in the individual treatment groups. Mean change from baseline in the urinary lactulose-to-mannitol (LAMA) ratio. Values are the geometric mean fold-ratio on day 14 over baseline (day 0). Vertical bars represent 95% confidence intervals. Dashed horizontal line indicates level for gluten-free control. G, gluten; P, placebo.
Figure 3
Figure 3
Change from baseline in gastrointestinal symptoms in the individual treatment groups as measured by the GSRS and CeD-GSRS. Mean (95% confidence interval) changes from baseline to day 14 in the total (a) Gastrointestinal Symptom Rating Scale (GSRS) scores and (b) Celiac Disease GSRS (CeD-GSRS) scores. n=9–13 per group. P values comparing larazotide acetate/gluten-challenge (G) groups to the placebo (P) drug/gluten-challenge group were calculated using an analysis of covariance model, with treatment as a fixed effect and the corresponding baseline value as a covariate.
Figure 4
Figure 4
Change in gastrointestinal symptoms as measured by the GSRS and CeD-GSRS during and after gluten challenge in the gluten challenge/placebo drug cohort compared to the aggregated gluten-free control cohorts and the Larazotide-treated gluten challenge groups. Time course of mean change from baseline in the total (a) Gastrointestinal Symptom Rating Scale (GSRS) score and (b) Celiac Disease (CeD-GSRS) scores. The gluten control group includes patients who received placebo drug and the gluten challenge (n=13). Gluten-free control includes patients who received placebo drug or 8 mg larazotide acetate and gluten placebo (n=20). Patients who received larazotide acetate and the gluten challenge were also combined into one group (n=38). P values were calculated using an analysis of covariance model with treatment as a fixed effect and the corresponding baseline value as a covariate.

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