School of Medicine, University of Tampere, Tampere University Hospital, Tampere, Finland.
Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital and School of Medicine, University of Tampere, Tampere, Finland; Department of Medicine, Seinäjoki Central Hospital, Seinäjoki, Finland.
Gastroenterology. 2014 Jun;146(7):1649-58. doi: 10.1053/j.gastro.2014.02.031. Epub 2014 Feb 25.
BACKGROUND & AIMS: Gluten ingestion leads to small intestinal mucosal injury in patients with celiac disease, necessitating strict life-long exclusion of dietary gluten. Despite adherence to a gluten-free diet, many patients remain symptomatic and still have small intestinal inflammation. In this case, nondietary therapies are needed. We investigated the ability of ALV003, a mixture of 2 recombinant gluten-specific proteases given orally, to protect patients with celiac disease from gluten-induced mucosal injury in a phase 2 trial. METHODS: We established the optimal daily dose of gluten to be used in a 6-week challenge study. Then, in the intervention study, adults with biopsy-proven celiac disease were randomly assigned to groups given ALV003 (n = 20) or placebo (n = 21) together with the daily gluten challenge. Duodenal biopsies were collected at baseline and after gluten challenge. The ratio of villus height to crypt depth and densities of intraepithelial lymphocytes were the primary end points. RESULTS: A daily dose of 2 g gluten was selected for the intervention study. Sixteen patients given ALV003 and 18 given placebo were eligible for efficacy evaluation. Biopsies from subjects in the placebo group showed evidence of mucosal injury after gluten challenge (mean villus height to crypt depth ratio changed from 2.8 before challenge to 2.0 afterward; P = .0007; density of CD3(+) intraepithelial lymphocytes changed from 61 to 91 cells/mm after challenge; P = .0003). However, no significant mucosal deterioration was observed in biopsies from the ALV003 group. Between groups, morphologic changes and CD3(+) intraepithelial lymphocyte counts differed significantly from baseline to week 6 (P = .0133 and P = .0123, respectively). There were no statistically significant differences in symptoms between groups. CONCLUSIONS: Based on a phase 2 trial, the glutenase ALV003 appears to attenuate gluten-induced small intestinal mucosal injury in patients with celiac disease in the context of an everyday gluten-free diet containing daily up to 2 g gluten. Clinicaltrial.gov, NUMBERS: NCT00959114 and NCT01255696.
背景与目的：麸质摄入可导致乳糜泻患者的小肠黏膜损伤，这需要严格终生禁食含麸质的饮食。尽管患者坚持无麸质饮食，但许多患者仍有症状，且小肠仍存在炎症。在这种情况下，需要非饮食疗法。我们研究了口服 2 种重组麸质特异性蛋白酶混合物 ALV003 能否在一项 2 期试验中保护乳糜泻患者免受麸质诱导的黏膜损伤。
方法：我们确定了用于 6 周挑战研究的最佳每日麸质剂量。然后，在干预研究中，活检证实的乳糜泻患者被随机分为 ALV003 组（n=20）或安慰剂组（n=21），两组均同时接受每日麸质挑战。在基线和麸质挑战后采集十二指肠活检。绒毛高度与隐窝深度的比值和上皮内淋巴细胞密度是主要终点。
结果：选择每日 2 g 麸质用于干预研究。20 名接受 ALV003 治疗和 18 名接受安慰剂治疗的患者符合疗效评估条件。接受安慰剂的患者的活检在麸质挑战后显示出黏膜损伤的证据（绒毛高度与隐窝深度的比值从挑战前的 2.8 变为挑战后的 2.0；P=0.0007；上皮内 CD3+淋巴细胞密度从挑战前的 61 个/毫米变为挑战后的 91 个/毫米；P=0.0003）。然而，在 ALV003 组的活检中未观察到明显的黏膜恶化。与基线相比，两组在第 6 周时形态变化和 CD3+上皮内淋巴细胞计数均有显著差异（P=0.0133 和 P=0.0123）。两组间症状无统计学差异。
结论：基于 2 期试验，在含有每日高达 2 g 麸质的无麸质饮食背景下，蛋白酶 ALV003 似乎可减轻乳糜泻患者的麸质诱导的小肠黏膜损伤。Clinicaltrial.gov，NCT00959114 和 NCT01255696。
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