Effect of Netazepide on Omeprazole-induced Changes in Chromogranin A and Gastrin

Dyspepsia Clinical Trial

Official title: Effect of Netazepide, a Gastrin/CCK2 Receptor Antagonist, on Esomeprazole-induced Increases in Circulating Gastrin and Chromogranin A, and on Esomeprazole Withdrawal in Healthy Subjects

Status Completed

Clinical Trial Summary

Hypergastrinaemia induced by proton pump inhibitor (PPI) treatment is reported to cause ECL-cell and parietal-cell hyperplasia, and rebound hyperacidity and dyspepsia after PPI withdrawal.

The objective of the study was to determine the dosage regimen of netazepide, a gastrin/CCK2 receptor antagonist, required to inhibit the trophic effects of PPI-induced hypergastrinaemia.

Six groups of 8 healthy subjects participated in a randomised, double-blind, placebo-controlled exploratory study of esomeprazole 40 mg daily for 28 days, and netazepide 1, 5 or 25 mg, or placebo daily during the last 14 days of esomeprazole dosing, or 14 days after esomeprazole withdrawal. Serum gastrin and plasma chromogranin A (CgA) were measured regularly from study start until at least 1 week after the last dose. Dyspepsia was monitored after esomeprazole withdrawal.

Clinical Trial Description

Non-clinical studies have shown that PPI-induced hypergastrinaemia leads to rebound gastric hyperacidity after PPI withdrawal. A gastrin/CCK2 receptor antagonist inhibits that response. Studies in healthy subjects and patients also suggest that PPI withdrawal leads to rebound hyperacidity, but the evidence is controversial. However, there is better evidence from studies in healthy subjects that PPI withdrawal can lead to dyspepsia.

The principal aims of this study were: to assess the effect of different dose regimens of netazepide on the increases in circulating gastrin and CgA induced by esomeprazole in healthy subjects; and to choose a dose regimen for future studies of esomeprazole withdrawal in patients. The secondary aims were: to assess if omeprazole withdrawal leads to dyspepsia, and if so whether it can be prevented by netazepide; and to assess the likelihood of an interaction between esomeprazole and netazepide. Gastrin and CgA are biomarkers of acid suppression and increased ECL-cell activity, respectively.

This was a randomised, double-blind, placebo-controlled, parallel-group, pilot study, in which six groups of eight healthy subjects took esomeprazole 40 mg daily for 28 days, and netazepide 1, 5 or 25 mg, or placebo, daily during the last 14 days of esomeprazole dosing, or the 14 days immediately following esomeprazole withdrawal (25 mg only). Gastrin and CgA were measured before the start of dosing until at least one week after completion of dosing. ;

Study Design

Allocation: Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Dyspepsia
• ECL-cell Hyperplasia
• Hyperplasia
• Parietal-cell Hyperplasia
• Rebound Hyperacidity

• NCT number: NCT02620696
• Study type: Interventional
• Source: Trio Medicines Ltd.
• Status: Completed
• Phase: Phase 1
• Start date: November 2009
• Completion date: September 2010