Hypergastrinemia has been associated with high grade dysplasia and adenocarcinoma in patients with Barrett’s esophagus (BE), and experimental studies suggest pro-inflammatory and pro-neoplastic effects of gastrin on BE. This is of potential concern, as BE patients are treated with medications that suppress gastric acid production, resulting in increased physiologic levels of gastrin. We aimed to determine whether treatment with the novel gastrin/CCK2 receptor antagonist netazepide reduces expression of markers associated with inflammation and neoplasia in BE. This was a randomized, double-blind, placebo-controlled trial of netazepide in patients with BE without dysplasia. Subjects were treated for 12 weeks, with endoscopic assessment at baseline and at end of treatment. The primary outcome was within-individual change in cellular proliferation as assessed by Ki67. Secondary analyses included changes in gene expression, assessed by RNA-sequencing, and safety and tolerability. A total of 20 subjects completed the study and were included in the analyses. There was no difference between arms in mean change in cellular proliferation (netazepide: +35.6 Ki67+ cells/ mm2, SD 620.7; placebo: +307.8 Ki67+ cells/ mm2, SD 640.3; p=0.35). Netazepide treatment resulted in increased expression of genes related to gastric phenotype (TFF2, MUC5B) and certain cancer-associated markers (REG3A, PAX9, MUC1), and decreased expression of intestinal markers MUC2, FABP1, FABP2, and CDX1. No serious adverse events related to study drug occurred. The gastrin/CCK2 receptor antagonist netazepide did not reduce cellular proliferation in patients with non-dysplastic BE. Further research should focus on the biological effects of gastrin in Barrett’s esophagus.Copyright ©2021, American Association for Cancer Research.