title: Dose-dependent effects of lesogaberan on reflux measures in patients with refractory gastroesophageal reflux disease: a randomized, placebo-controlled study.
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.
  
  
  BACKGROUND
  ClinicalTrials.gov identifier: NCT01043185.
authors.affiliation: Oklahoma Foundation for Digestive Research, 535 NW 9th Street, Suite 325, Oklahoma City, OK, USA. Philip-Miner@ofdr.com.
authors.forename: Philip B
authors.initials: PB
authors.lastname: Miner
authors.forename: Debra G
authors.initials: DG
authors.lastname: Silberg
authors.forename: Magnus
authors.initials: M
authors.lastname: Ruth
authors.forename: Frank
authors.initials: F
authors.lastname: Miller
authors.forename: John
authors.initials: J
authors.lastname: Pandolfino
mesh_terms: D000328:Adult; D000368:Aged; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004947:Esophagus / Q000503:physiopathology; D005260:Female; D058785:GABA-A Receptor Agonists / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D005764:Gastroesophageal Reflux / Q000188:drug therapy* / Q000503:physiopathology; D005765:Gastrointestinal Agents / Q000008:administration & dosage*; D006261:Headache / Q000139:chemically induced; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D010721:Phosphinic Acids / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011437:Propylamines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D058785:GABA-A Receptor Agonists; D005765:Gastrointestinal Agents; D010721:Phosphinic Acids; D011437:Propylamines; C545087:lesogaberan