A Novel Partial 5HT3 Agonist DDP733 after a Standard Refluxogenic Meal Reduces Reflux Events: A Randomized, Double-Blind, Placebo-Controlled Pharmacodynamic Study

Abstract

Listen

Translate article

Purpose: Transient lower esophageal sphincter (LES) relaxations are the major cause of gastro-esophageal reflux. DDP733, a selective partial agonist at 5HT3 receptors, increases LES in experimental animal models. However, its effect on gastroesophageal reflux or LESP in humans is unknown. Aims: To evaluate the effect of DDP733 on reflux episodes in healthy volunteers receiving a refluxogenic meal, and to assess the safety and tolerability of DDP 733. Methods: A randomized, double-blind, placebo-controlled crossover study evaluated the pharmacodynamic effects of DDP733. Subjects were randomized on a 1:2:1 basis to one of three dose levels of DDP733 (0.5 mg, 0.8 mg, 1.4 mg), and randomized to the order of administration of placebo or active drug. Healthy subjects underwent manometry, and intraesophageal multichannel intraluminal impedance and pH after a standard refluxogenic meal. For evaluating the safety and tolerability of DDP733, each subject took drug or placebo (three times daily) for one week. A pooled analysis of variance, of the within subject deltas (placebo-drug) over all three dose groups with dose specific tests (α= 0.017) for no change were examined. Results: DDP733 0.5 mg significantly reduced the rate of reflux episodes after refluxogenic meal from 10.4 (±2.2) on placebo to 6.3 (±1.2) on drug over a 2 hour period. However, DDP733 0.8 mg and 1.4 mg had no significant effect on reducing the number of reflux episodes (table). Significant differences in LESP and the proportion of time pH was < 4 (placebo-drug) after a reflexogenic meal were not detected. No serious adverse events on DDP733 were reported. Conclusion: In healthy subjects, the partial 5HT3 agonist DDP733 at a dose of 0.5 mg significantly reduces the rate of reflux events, but did not result in a significant change in LES pressure at one hour post dosing.Table: Reflux events, post treatment mean LESP, and proportion time that time pH < 4 on drug or placebo (Mean ± SEM)