Purpose: To determine the relationship between esomeprazole dose and symptom resolution in patients with symptomatic GERD, prior response to antacids/acid suppression therapy, and a positive acid perfusion test. Methods: This randomized, double-blind, proof-of-concept study (D9612L00106, NCT00206024) included patients aged 18-75 yrs with a history of both heartburn for ≥6 mo and symptomatic response to antacids/acid suppression therapy. Patients recorded heartburn symptoms during a 2-wk run-in period using an electronic diary. At the end of the run-in period, those who had moderate to severe heartburn ≥3 d/wk and who had not used acid suppression therapy had an acid perfusion test. Those with a positive acid perfusion test were then randomized to 1 of 3 dosing regimens for 4 wk: esomeprazole 20 or 40 mg daily or 40 mg twice daily. Primary efficacy measures included proportion of patients with sustained heartburn resolution for 7 d and heartburn relief during week 4 and secondary measures included heartburn-free days/nights. Results: Of the 368 patients in the intention-to-treat population, most were white women; mean age was 45 y, and mean body mass index was 29.8 kg/m2. The proportion of patients with sustained heartburn resolution was similar for all 3 groups as was heartburn relief during week 4 (Table). Nocturnal heartburn control in the esomeprazole 40 mg twice daily group showed improvement compared with the other 2 groups but was not statistically significant.Table: Table. Efficacy of esomeprazole in the treatment of acid-related heartburnConclusion: Treatment with all esomeprazole doses provided reasonable and similar rates of sustained heartburn relief, suggesting a plateau effect in terms of clinical response to acid suppression with proton pump inhibitor (PPI) therapy. Despite an attempt to enrich the study population through the use of history of response to acid suppression and positive acid perfusion test, the study did not show an increased symptomatic response to increased doses of drug. However, all doses of esomeprazole did provide reasonable and similar rates of sustained heartburn relief, suggesting a plateau effect in terms of the clinical response to acid suppression with PPI therapy. Potential areas of future research include studying the effect of varying PPI dose and timing of administration on acid control in individual patients and assessing the potential value of managing other components of GERD besides acid control. Disclosure: Dr Orlando has or has had in the recent past financial relationships (consulting, lecture bureau, research support, stock ownership) with Amicus Therapeutics, AstraZeneca LP, Boston Scientific, Merck, Novartis, Pfizer, Procter & Gamble, Santarus, and Sirna. Drs Illueca and Liu are employees of AstraZeneca LP. This research was supported by an industry grant from Study funded by AstraZeneca LP.