Miner et al. BMC Gastroenterology 2014, 14:188 http://www.biomedcentral.com/1471-230X/14/188 RESEARCH ARTICLE Open Access Dose-dependent effects of lesogaberan on reflux measures in patients with refractory gastroesophageal reflux disease: a randomized, placebo-controlled study Philip B Miner Jr1*, Debra G Silberg2, Magnus Ruth3, Frank Miller4 and John Pandolfino5 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. Keywords: Gastroesophageal reflux, Lower esophageal sphincter, GABA-B agonist, Dose–response, Clinical study Background pharmacological treatments for GERD focus on the Gastroesophageal reflux disease (GERD) is widespread, suppression of gastric acid secretion by the use of proton affecting approximately 10–20% of people in Europe and pump inhibitors (PPIs). Although PPI therapy is effective in North America [1]. The primary symptoms of GERD – most patients with GERD, approximately 20–30% continue heartburn and regurgitation – are thought to occur because to experience reflux symptoms despite PPI treatment [3]. the lower esophagus is exposed to the acid contents of the TLESRs are thought to be responsible for about 80% of stomach, predominantly as a result of transient lower reflux episodes in patients with GERD, and are therefore a esophageal sphincter relaxations (TLESRs) [2]. Current suitable target for treatment [4,5]. This strategy may be particularly appropriate for patients who have reflux symp- * Correspondence: [email protected] toms despite taking a PPI because such symptoms, when 1Oklahoma Foundation for Digestive Research, 535 NW 9th Street, Suite 325, not attributed to suboptimal PPI therapy and/or poor PPI Oklahoma City, OK, USA Full list of author information is available at the end of the article © 2014 Miner et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Miner et al. BMC Gastroenterology 2014, 14:188 Page 2 of 12 http://www.biomedcentral.com/1471-230X/14/188 treatment adherence, may be elicited by exposure of the have a narrow therapeutic window (such as warfarin or esophagus to weakly acid or non-acid reflux [3,6-8]. digoxin) or that could interfere with the pharmacody- The stimulation of γ-aminobutyric acid type B receptors namic effects of lesogaberan (such as baclofen or supple- (GABAB), both peripherally and centrally, has been shown ments containing GABA), alter gastrointestinal symptoms to inhibit TLESRs [9]. The GABAB agonist baclofen has (such as type 2 histamine receptor agonists) or damage been used to inhibit TLESRs and reflux episodes, both in the mucosal lining of the gastrointestinal tract (such as healthy individuals and in patients with GERD, but the non-steroidal anti-inflammatory drugs, or acetylsalicylic central effects of tiredness and sleepiness have prevented acid in doses > 162 mg/day). Individuals were also ex- widespread use of this drug [10-13]. cluded if they had clinically significant disorders that The novel GABAB agonist lesogaberan (AZD3355) could interfere with the study or compromise patients’ significantly inhibits TLESRs and reflux episodes in safety (e.g. cardiovascular, respiratory, hepatic, renal, meta- humans, but has been assessed only as a single 0.8 mg/ bolic, psychiatric or neurological disorders, or gastrointes- kg dose and a twice-daily 65 mg dose [14,15]. The aim tinal disorders besides GERD), or had a history of syncope, of this study was to explore the dose–response effects heart disease, malignant disease, drug addiction or abuse, of lesogaberan, relative to placebo, on reflux variables, electrolyte imbalances or severe allergic or hypersensitive and on the pharmacokinetics, and safety and tolerability reactions. Pregnant or breastfeeding women were also profiles, in patients with GERD who have symptoms excluded from the study (women of childbearing age were despite PPI therapy. required to use effective contraceptive measures). Methods Study drugs, design and ethics Study participants This was a randomized, double-blind, placebo-controlled, This study was carried out at a single centre in the USA four-way crossover, phase 2a study. An outline of the study (Oklahoma Foundation for Digestive Research) and all design is shown in Figure 1. Patients were randomized to patients gave written, informed consent before entering receive one of 10 treatment sequences each consisting of the study. placebo and three of the four different lesogaberan doses Participants were all patients with GERD who had a par- (30, 90, 120 and 240 mg). These were given on different tial response to PPI treatment. Criteria used to identify days, each separated by a 7–28-day washout period. This this group of men and women were: a history of GERD washout period far exceeds the likely maximum duration symptoms of at least 6 months in addition to ongoing of pharmacological activity, which is conventionally esti- symptoms [defined as ≥ 3 days with at least moderate mated as five times the pharmacological half-life of a drug heartburn (burning feeling behind the breastbone) or ≥ (which, for lesogaberan, is approximately 11–13 h) [16], 3 days with at least moderate regurgitation (unpleasant meaning that at maximum only 0.01% of the peak concen- movement of material upwards from the stomach)] tration (Cmax) remains at the end of the wash-out period. reported in the 7-day recall Reflux Symptom Question- Each dose was given twice over a 24-h period in the form naire (RESQ-7) administered within 21 days of study of modified-release capsules: one taken 1 h before break- entry; continuous treatment in the 4 weeks before fast after fasting the night before, and the other taken 1 h enrolment with daily, optimized and unchanged PPI ther- before dinner. (Note that patients fasted overnight before apy, with doses according to the US label for any GERD each study period: no food after 22:00 and no fluids indication (an optimized PPI treatment is a treatment that, after 24:00.) Treatment with patients’ usual, regular and according to the investigator’sjudgement,cannotbe optimized dose of PPI was continued throughout the improved further by changing brand or dose regimen); study. and completion of 8 weeks of treatment with a PPI in The study (ClinicalTrials.gov identifier: NCT01043185) patients with reflux esophagitis verified by endoscopy in was designed and performed in accordance with ethical the 8 weeks before enrolment. Participants were also principles originating in the Declaration of Helsinki, required to be healthy (other than having GERD) men or and the study was consistent with guidelines of the women, aged 18–70 years, with a body mass index (BMI) International Conference on Harmonisation and Good of 18.5–35.0 kg/m2, and with clinically normal physical Clinical Practice, regulatory requirements, and the findings and laboratory values at the pre-entry visit. In AstraZeneca policy on bioethics and human biological addition, participants had to have a PPI prescription with samples. In addition, the University of Oklahoma Health refills covering the entire study period, or physician instruc- Sciences Centre’s Institutional Review Board approved the tions to use equivalent over-the-counter PPI medication. study protocol. The investigator obtained signed informed Patients were excluded if they had shown no improve- consent from the potential patients, assigned them unique ment in GERD symptoms during PPI therapy. Other enrolment numbers, determined patient eligibility and exclusion criteria were the concomitant use of drugs that assigned eligible patients unique randomization codes. Miner et al. BMC Gastroenterology 2014, 14:188 Page 3 of 12 http://www.biomedcentral.com/1471-230X/14/188 Visit 1 Visit 2 Visit 3 Visit 4 Visit 5 Visit 6 > 21 days 7–28 days 7–28 days 7–28 days 5–10 days Pre-entry Study period 1 Study period 2 Study period 3 Study period 4 Follow-up Placebo or Placebo or Placebo or Placebo or R 30 mg or 30 mg or 30 mg or 30 mg or 90 mg or 90 mg or 90 mg or 90 mg or 120 mg or 120 mg or 120 mg or 120 mg or 240 mg 240 mg 240 mg 240 mg Figure 1 Study design.