Dose-dependent effects of lesogaberan on reflux measures in patients with refractory gastroesophageal reflux disease: a randomized, placebo-controlled study

Philip B Miner Jr, Debra G Silberg, Magnus Ruth, Frank Miller, John Pandolfino, Philip B Miner Jr, Debra G Silberg, Magnus Ruth, Frank Miller, John Pandolfino

Abstract

Background: The γ-aminobutyric acid type B-receptor agonist lesogaberan (AZD3355) has been developed for use in patients with gastroesophageal reflux disease (GERD) symptoms despite proton pump inhibitor (PPI) therapy (partial responders). This study aimed to explore the dose-response effect of lesogaberan on reflux episodes in partial responders.

Methods: In this randomized, single-centre, double-blind, crossover, placebo-controlled study, partial responders taking optimised PPI therapy were given 30, 90, 120 and 240 mg doses of lesogaberan. Each dose was given twice (12 h apart) during a 24-h period, during which impedance-pH measurements were taken.

Results: Twenty-five patients were included in the efficacy analysis and 27 in the safety analysis. The effect of lesogaberan on the mean number of reflux episodes was dose-dependent, and all doses significantly reduced the mean number of reflux episodes relative to placebo. Lesogaberan also dose-dependently reduced the mean number of acid reflux episodes (except the 30 mg dose) and weakly acid reflux episodes (all doses) significantly, relative to placebo. Regardless of dose, lesogaberan had a similar effect on the percentage of time with esophageal pH < 4 [mean reduction: 68.5% (30 mg), 54.2% (90 mg), 65.9% (120 mg), 72.1% (240 mg); p < 0.05 except 90 mg dose]. No adverse events led to discontinuation and no serious adverse events occurred during active treatment.

Conclusions: Lesogaberan inhibited reflux in a dose-dependent manner in partial responders taking optimised PPI therapy, and these effects were significant versus placebo. All lesogaberan doses were well tolerated and were not associated with clinically relevant adverse events.

Trial registration: ClinicalTrials.gov identifier: NCT01043185.

Figures

Figure 1
Figure 1
Study design. Patients were assigned to four of five treatments by being randomized (R) to one of the following treatment sequences: EABC (n = 2), ABCE (n = 3), BCED (n = 3), CEDB (n = 3), EDBA (n = 3), DABE (n = 3), ABEC (n = 2), BECD (n = 2), ECAD (n = 3) or CADE (n = 3), where A, B, C and D correspond to lesogaberan 30, 90, 120 and 240 mg, respectively, and E corresponds to placebo. The randomization was performed in blocks of consecutive patient numbers.
Figure 2
Figure 2
Study flow. In total, 27 patients were randomised to receive placebo and 3 of the 4 doses of lesogaberan, based on the randomly assigned treatment sequences shown in Figure  1 (26 patients completed the study). Overall, 7 poor-quality traces were excluded from the final evaluable dataset used to estimate the dose–response effects of lesogaberan (primary outcome).
Figure 3
Figure 3
Observed effects (efficacy analysis set) of lesogaberan 30, 90, 120 and 240 mg compared with placebo on: (A) the total number of reflux episodes; (B) the number of acid and weakly acid reflux episodes; and (C) the number of pure liquid and mixed liquid/gas reflux episodes. Data are presented as geometric means with 95% confidence intervals.
Figure 4
Figure 4
Observed effects (efficacy analysis set) of lesogaberan 30, 90, 120 and 240 mg compared with placebo on: (A) the proximal extent of reflux; and (B) the proportion of time with esophageal pH < 4. Data are presented as geometric means with 95% confidence intervals.
Figure 5
Figure 5
Arithmetic mean plasma concentration of lesogaberan. Lesogaberan was administered as doses of 30, 90, 120 or 240 mg twice daily (b.i.d.) over a period of 24 h (pharmacokinetics analysis set).
Figure 6
Figure 6
Number of reflux episodes over a period of 24 h. Estimation using a mixed-effect Emax model of (A), the predicted exposure–response curve with 95% CI curves (intersection of efficacy and pharmacokinetics analysis set) and (B), the dose–response curve with 95% CIs (efficacy analysis set) for lesogaberan. CI, confidence interval.

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Pre-publication history
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