Randomised clinical trial: the 5-HT4 agonist revexepride in patients with gastro-oesophageal reflux disease who have persistent symptoms despite PPI therapy

N J Shaheen, J Adler, S Dedrie, D Johnson, P Malfertheiner, P Miner, A Meulemans, L Poole, J Tack, L Thielemans, S Troy, N Vakil, F Zerbib, M Ruth, N J Shaheen, J Adler, S Dedrie, D Johnson, P Malfertheiner, P Miner, A Meulemans, L Poole, J Tack, L Thielemans, S Troy, N Vakil, F Zerbib, M Ruth

Abstract

Background: A substantial proportion of patients with gastro-oesophageal reflux disease (GERD) have only a partial response to proton pump inhibitor (PPI) therapy. Prokinetic drugs may improve reflux symptoms by enhancing oesophageal motility and gastric emptying.

Aim: To evaluate the effect of revexepride, a novel prokinetic 5-hydroxytryptamine type 4 (5-HT4 ) receptor agonist, compared with placebo, in patients with GERD who have a partial response to PPIs.

Methods: A phase 2b, double-blind, parallel-group study was conducted, in which patients were randomised to one of three revexepride treatment groups (0.1, 0.5 and 2.0 mg three times daily) or placebo (1:1:1:1 ratio). Daily e-diary data captured patients' symptoms over an 8-week treatment period. The primary efficacy outcome was the weekly percentage of regurgitation-free days in the second half of the study (weeks 5-8).

Results: In total, 480 patients were randomised and 477 received treatment (mean age 47.9 years; 61% women). The mean percentage of regurgitation-free days increased from baseline (range, 15.0-18.8%) to week 8 (62.3-70.5%) in all four study arms; however, there were no statistically significant differences in this change between placebo and the three treatment arms. No dose-dependent relationship in treatment effect was observed for any of the study endpoints. The incidence of treatment-emergent adverse events (TEAEs) was revexepride dose-dependent. Only one serious TEAE occurred and none resulted in death.

Conclusions: Revexepride was no more effective than placebo in controlling regurgitation in patients with GERD symptoms partially responsive to PPIs. Revexepride was well tolerated. ClinicalTrials.gov Identifier: NCT01472939.

© 2015 Shire Development LLC. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.

Figures

Figure 1
Figure 1
Study design. PPI, proton pump inhibitor.
Figure 2
Figure 2
Study analysis population. n, number of patients.
Figure 3
Figure 3
Mean (± standard deviation) change from baseline in percentage of (a) regurgitation‐free and (b) heartburn‐free days by visit and treatment group (full analysis set). Regurgitation: differences in change from baseline between placebo and the three revexepride treatment groups were not statistically significant. Heartburn: there was a statistically significant difference (P < 0.05) between revexepride 0.5 mg and placebo only.
Figure 4
Figure 4
Percentage (± SE) of patients with a reduction of 3 or more days with (a) regurgitation and (b) heartburn, by visit and by treatment group (full analysis set). Regurgitation: differences in change from baseline between placebo and the three revexepride treatment groups were not statistically significant. Heartburn: there was a statistically significant difference (P < 0.05) between revexepride 0.5 mg and placebo only.

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