title: Randomised clinical trial: arbaclofen placarbil in gastro-oesophageal reflux disease--insights into study design for transient lower sphincter relaxation inhibitors.
abstract: BACKGROUND
  Arbaclofen placarbil is a pro-drug of the gamma-aminobutyric acid-B agonist R-baclofen that has been shown to reduce reflux episodes in patients with gastro-oesophageal reflux disease (GERD).
  
  
  OBJECTIVE
  To evaluate the efficacy and safety of arbaclofen placarbil vs. placebo as adjunctive therapy in subjects with troublesome GERD symptoms despite therapy with once-daily doses of a proton pump inhibitor (PPI) and to identify the characteristics of patients who were responders.
  
  
  METHODS
  Patients (n = 460) with symptomatic GERD experiencing troublesome symptoms on once-daily PPI therapy were enrolled in this phase II, randomised, multicentre, double-blind, placebo-controlled, dose-ranging study. Patients were randomised to receive placebo or arbaclofen placarbil (20 or 40 mg once daily, 20 or 30 mg twice daily) with their current PPI for 6 weeks. Patients recorded heartburn and other GERD symptoms in a daily diary and rated severity of each event. The primary endpoint was percent change from baseline in heartburn events per week.
  
  
  RESULTS
  In the primary analysis, there was no significant difference between arbaclofen placarbil and placebo. Post hoc analyses removing mild and very mild heartburn events resulted in greater percent reductions for all arbaclofen placarbil doses with nominal P values <0.05 for each dose compared with placebo. There was a dose-related increase for the most common adverse events.
  
  
  CONCLUSIONS
  Arbaclofen placarbil was not superior to placebo in the primary analysis. Post hoc analyses suggest that subjects with more clinically relevant moderate or severe symptoms are more likely to respond to arbaclofen placarbil (clinicaltrials.gov NCT00978016).
authors.affiliation: University of Wisconsin School of Medicine and Public Health, Milwaukee, WI, USA. nimish.vakil@gmail.com
authors.forename: N B
authors.initials: NB
authors.lastname: Vakil
authors.forename: F J
authors.initials: FJ
authors.lastname: Huff
authors.forename: K C
authors.initials: KC
authors.lastname: Cundy
mesh_terms: D000328:Adult; D001418:Baclofen / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D049630:Esophageal Sphincter, Lower / Q000187:drug effects; D005260:Female; D058786:GABA-B Receptor Agonists / Q000009:adverse effects / Q000627:therapeutic use*; D005764:Gastroesophageal Reflux / Q000188:drug therapy*; D006356:Heartburn / Q000188:drug therapy; D006801:Humans; D008297:Male; D008875:Middle Aged; D009125:Muscle Relaxants, Central / Q000009:adverse effects / Q000627:therapeutic use*; D054328:Proton Pump Inhibitors / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D058786:GABA-B Receptor Agonists; D009125:Muscle Relaxants, Central; D054328:Proton Pump Inhibitors; D001418:Baclofen; C543531:arbaclofen placarbil