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Objectives: It is thought that esophageal hypersensitivity in combination with an impaired mucosal barrier function contributes to PPI-resistant reflux symptoms. Ziverel, a bioadhesive agent that coats the esophageal wall, was shown to have a positive effect on reflux symptoms. However, the mechanisms of action are unclear. We aimed to assess the effect of Ziverel on esophageal sensitivity to acid and mucosal barrier function., Methods: We performed a double-blind randomized placebo-controlled crossover trial in PPI-refractory patients with reflux symptoms. Patients were assigned (1:1) to 14 days of Ziverel followed by 14 days of placebo or opposite treatment order. The effect was evaluated using acid perfusion tests, an upper endoscopy with electrical tissue impedance spectroscopy (ETIS) and esophageal biopsies. The primary outcome was the esophageal sensitivity based on perfusion sensitivity score. Secondary outcomes included mucosal barrier function and reflux symptoms and correlations between the different outcomes., Results: Perfusion sensitivity score was not significantly different during treatment with Ziverel (106 (73-115)) and placebo (102 (67-110)) ( p  = 0.508) along with total RDQ score (2.6 (1.9-3.3) vs 2.8 (1.6-3.5) p  = 0.456). ETIS showed comparable values during treatment with Ziverel (13514 (8846-19734)Ω·m) and placebo (13217 (9127-24942)Ω·m ( p  = 0.650)). Comparing Ziverel and placebo no difference was seen in transepithelial electrical resistance (TEER) 203 (163-267) Ω.cm 2 vs 205 (176-240) Ω.cm 2 ( p  = 0.445) and fluorescein flux 775 (17-6964) nmol/cm 2 /h vs 187 (4-12209) nmol/cm 2 /h ( p  = 0.638)., Conclusion: Ziverel did not show a benefit on acid sensitivity, reflux symptoms or esophageal mucosal integrity compared to placebo in PPI-refractory patients with reflux symptoms. Trial registration : Netherlands Trial Register number: NL7670.