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Gut 62:1248-1255 doi:10.1136/gutjnl-2012-302737
  • Oesophagus
  • Original article

Efficacy and safety of lesogaberan in gastro-oesophageal reflux disease: a randomised controlled trial

  1. Debra G Silberg3
  1. 1Center for Esophageal Diseases and Swallowing, Department of Medicine, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA
  2. 2AstraZeneca R&D, Mölndal, Sweden
  3. 3AstraZeneca R&D, Wilmington, Delaware, USA
  1. Correspondence to Dr Nicholas J Shaheen, Center for Esophageal Diseases and Swallowing, University of North Carolina, CB 7080, Chapel Hill, NC 27599, USA; nshaheen{at}med.unc.edu
  1. Contributors All authors contributed to the study design and data interpretation, and provided input on the manuscript. AstraZeneca R&D, Mölndal, Sweden, was involved in the data collection, analysis and interpretation. NS was the principal investigator, and NS, HD and DS oversaw the conduct of the study. KB undertook all statistical data analysis. MK was responsible for the patient-reported outcomes measure. The corresponding author had full access to all of the data and takes full responsibility for the veracity of the data and statistical analysis. Writing support funded by AstraZeneca was provided by Dr Stephen Sweet of Oxford PharmaGenesis ™ Ltd.

  • Revised 23 May 2012
  • Accepted 25 May 2012
  • Published Online First 23 June 2012

Abstract

Objective Lesogaberan (AZD3355) is a novel γ-aminobutyric acid B-type receptor agonist designed to treat gastro-oesophageal reflux disease (GERD) by inhibiting transient lower oesophageal sphincter relaxations. A randomised, double-blind, placebo-controlled, multi-centre phase IIb study was performed to assess the efficacy and safety of lesogaberan as an add-on to proton pump inhibitor (PPI) therapy in patients with GERD who are partially responsive to PPI therapy (ClinicalTrials.gov reference: NCT01005251).

Design In total, 661 patients were randomised to receive 4 weeks of placebo or 60, 120, 180 or 240 mg of lesogaberan twice daily, in addition to ongoing PPI therapy. Symptoms were measured using the Reflux Symptom Questionnaire electronic Diary. Response to treatment was defined as having an average of ≥3 additional days per week of not more than mild GERD symptoms during treatment compared with baseline.

Results In the primary analysis, 20.9%, 25.6%, 23.5% and 26.2% of patients responded to the 60, 120, 180 and 240 mg twice daily lesogaberan doses, respectively, and 17.9% responded to placebo. The response to the 240 mg twice daily dose was statistically significantly greater than the response to placebo using a one-sided test at the predefined significance level of p<0.1. However, the absolute increases in the proportions of patients who responded to lesogaberan compared with placebo were low. Lesogaberan was generally well tolerated, although six patients receiving lesogaberan developed reversible elevated alanine transaminase levels.

Conclusions In patients with GERD symptoms partially responsive to PPI therapy, lesogaberan was only marginally superior to placebo in achieving an improvement in symptoms.

Footnotes

  • Funding This study was supported by AstraZeneca R&D, Mölndal, Sweden.

  • Competing interests Nicholas Shaheen has received grant/research support from AstraZeneca, BÂRRX Medical, Procter & Gamble Pharmaceuticals, Oncoscope, Inc., Takeda Pharmaceutical Company and CSA Medical, Inc., and has received consulting fees from Takeda Pharmaceutical Company, CSA Medical, Inc., AstraZeneca Pharmaceuticals LP, Oncoscope, Inc., NeoGenomics and Shire Pharmaceuticals Inc. Hans Denison, Karin Björck and Maria Karlsson are employees of AstraZeneca R&D, Mölndal, Sweden. Debra Silberg was an employee of AstraZeneca R&D, Wilmington, DE, USA, at the time the study was carried out.

  • Patient consent All patients provided informed consent before the initiation of study-specific procedures.

  • Ethics approval The study was carried out in accordance with the Declaration of Helsinki. A three-member Data Safety and Monitoring Board with no affiliation to the sponsor or other involvement in the trial assessed interim safety data.

  • Provenance and peer review Not commissioned; externally peer reviewed.