Alimentary Pharmacology & Therapeutics SUMMARY

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1 Alimentary Pharmacology & Therapeutics Comparison of the effects of immediate-release omeprazole oral suspension, delayed-release lansoprazole capsules and delayedrelease esomeprazole capsules on nocturnal gastric acidity after bedtime dosing in patients with night-time GERD symptoms P. O. KATZ*, F. K. KOCH, E.D.BALLARD, R.G.BAGIN, T.C.GAUTILLE, G.C.CHECANI, D. L. HOGANà &V.S.V.PRATHAà *Albert Einstein Medical Center, Philadelphia, PA, USA; Santarus Inc., San Diego, CA, USA; àclinical Applications Laboratories Inc., San Diego, CA, USA Correspondence to: Dr P. O. Katz, Department of Medicine, Albert Einstein Medical Center, Old York Road, Klein Building, Suite, Philadelphia, PA 9-, USA. Publication data Submitted September First decision October Resubmitted November Accepted November SUMMARY Background Gastro-oesophageal reflux disease (GERD) patients on proton pump inhibitors before breakfast or dinner have acid recovery at night. Bedtime immediate-release omeprazole (IR-OME) demonstrated better control of nocturnal ph than pantoprazole before dinner. Aim To compare repeated once daily bedtime dosing of IR-OME, lansoprazole and esomeprazole on nocturnal gastric acidity. Methods Open-label, randomized, crossover study enrolling patients with nocturnal GERD symptoms comparing IR-OME, lansoprazole and esomeprazole at steady state for nocturnal acid breakthrough (NAB), percentage of time with gastric ph > and median gastric ph. Results Onset of nocturnal acid control with IR-OME was rapid. During the first half of the night, percentage of time with gastric ph > and median gastric ph were significantly higher after IR-OME compared to esomeprazole or lansoprazole (P <., both comparisons). Over the -h night-time period, acid control with IR-OME was significantly better than lansoprazole (P <.), and comparable to esomeprazole. IR-OME reduced NAB compared with esomeprazole and lansoprazole (% vs. 9% and 9%; P <., both comparisons). Conclusions Bedtime IR-OME provided more rapid control of night-time gastric ph and decreased NAB compared with esomeprazole and lansoprazole. Nocturnal acid control with IR-OME was superior to lansoprazole and comparable to esomeprazole. Bedtime dosing with IR-OME may be effective for patients with night-time heartburn. Aliment Pharmacol Ther, 9 ª The Authors 9 doi:./j.-..9.x

2 9 P. O. KATZ et al. INTRODUCTION Recent findings suggest that reflux episodes occur primarily during the first half of the sleeping period. This is consistent with the circadian rhythm of gastric acid secretion that is characterized by increasing acid output in the late evening, reaching a maximum in the early night-time hours and diminishing towards the early morning., This rhythm has been described in healthy subjects, even when receiving a proton pump inhibitor (PPI) twice daily, and in patients with gastro-oesophageal reflux disease (GERD). Gastro-oesophageal reflux disease is generally considered to be one of the most prevalent conditions affecting the gastrointestinal (GI) tract. An estimated % of the US population experience the classic reflux symptoms of heartburn or regurgitation at least weekly, and at least % experience heartburn on a monthly basis. Approximately % of individuals with frequent heartburn experience heartburn at night, and 9% are awakened at night by coughing or choking resulting from fluid or food regurgitation. 9 Studies have shown that night-time gastrooesophageal reflux affects sleep quality and daytime functioning. Single daily doses of a PPI provide acid suppression sufficient to treat symptoms of GERD; however, when dosed once daily before breakfast, all PPIs are unable to effectively control the increasing gastric acidity that occurs during the night. Alternative treatment strategies, including dosing of PPIs prior to the evening meal and twice daily dosing (prior to breakfast and prior to dinner), have not resulted in complete control of nocturnal gastric acidity. Immediate-release omeprazole (IR-OME) contains non-enteric coated omeprazole, and an antacid buffer that protects the omeprazole from gastric acid degradation in the stomach and allows for rapid absorption. IR-OME has demonstrated effective control of gastric acidity when dosed on an empty stomach at bedtime. In a recent open-label study, IR-OME suspension and delayed-release pantoprazole were compared for their effects on nocturnal gastric acidity. This study showed that IR-OME dosed once daily at bedtime produced a significantly greater reduction in nocturnal gastric acidity than either repeated once daily (predinner) or twice daily (pre-breakfast and at bedtime) dosing of pantoprazole. The unique ability of IR-OME to produce rapid and sustained control of nocturnal gastric acidity when administered once daily at bedtime may be of significance for those patients who require better acid control at night-time. The current study was designed to compare the effects of IR-OME with those of two delayed-release PPIs, lansoprazole and esomeprazole, on nocturnal gastric acidity in GERD patients with night-time symptoms, when all three PPIs were dosed at bedtime. Because of the physiological fluctuations in acid secretion during the night, the acid suppressive effects of bedtime dosing of PPIs were evaluated for cumulative night-time intervals. In addition, for a better understanding of the pharmacodynamic (PD) profiles of immediate-release and delayed-release PPIs when dosed at bedtime, omeprazole pharmacokinetics were evaluated for IR-OME and esomeprazole. METHODS Patients Non-Asian subjects at least years of age were included in this study if they had a history of GERD at least partially responsive to antacids or acid suppressants, and had recurrent night-time symptoms for the previous months, were able to tolerate the placement of a nasogastric ph probe, and had a baseline gastric ph. prior to randomization. Exclusion criteria included any concurrent GI diseases or conditions other than GERD, a significant history of GI diseases or conditions in the past years, any history of gastric surgery or any other significant unstable illness, any use of PPIs within days prior to the study, or any use of histamine- receptor antagonists (HRA) or anticholinergic drugs within days prior to the study. The study was approved by an independent institutional review board. Patients were enrolled irrespective of Helicobacter pylori status (assessed at screening), as in clinical practice, GERD patients are not routinely screened for H. pylori prior to initiation of PPI treatment. Study design and randomization This was a single-site, open-label, randomized, threeperiod crossover study designed by P. Katz, V. Pratha, D. Hogan and Santarus Inc. and performed at Clinical Applications Laboratories in San Diego, California. Following a screening period of up to days, patients were randomly assigned to one of three treat-

3 CONTROL OF NOCTURNAL GASTRIC ACIDITY IN PATIENTS WITH NIGHT-TIME HEARTBURN 99 ment sequences to receive IR-OME mg (Zegerid; Santarus Inc., San Diego, CA, USA), lansoprazole mg (Prevacid; TAP Pharmaceuticals Inc., Lake Forest, IL, USA) and esomeprazole mg (Nexium; Astra- Zeneca, Wilmington, DE, USA). Patients received three -day dosing regimens according to their treatment group assignments. During each period, patients took study drug on an empty stomach (approximately h after dinner) once daily at bedtime (approximately : hours). From day through day, patients were allowed to eat a snack at : hours. Patients remained in the clinic from the afternoon of day until the morning of day. On days and, administration of study drug was supervised to ensure compliance. All meals administered in the clinic were standardized and served at the same time (:, : and : hours). Following a - to -day washout between treatment periods, patients were crossed over to one of the alternative treatments as determined by randomization. Assessment of gastric acidity The primary endpoint of this study was the occurrence of nocturnal acid breakthrough (NAB), defined as gastric ph < continuously for more than h during the night-time from : to : hours (adapted from the original definition according to Peghini et al.). The effect of each PPI on nocturnal gastric acidity was also assessed by evaluating the percentage of time with gastric ph > and median gastric ph in cumulative -h increments during the night-time period. In addition to analysis of nocturnal gastric acidity, the percentage of time with gastric ph > and median gastric ph were also calculated over h. These analyses were prospectively defined in the statistical analysis plan prior to study initiation. Evaluation of integrated gastric acidity (IGA), the acidity over a specific period of time, and the percentage of patients with median gastric ph >, were conducted as post hoc analyses. Study procedures and endpoints Gastric ph recording Gastric ph was recorded every s using an ambulatory ph recording system (Digitrapper Mark III; Medtronic Gastroenterology, Shoreview, MN, USA) with a disposable dual ph catheter containing an internal reference (Zinetics ; Medtronic Gastroenterology) calibrated at the start of the study to a ph of and a ph of using standard solutions. The software used to process the ph data (PolyGram for Windows v..; Medtronic) had been updated to adjust all ph values for the difference between probe calibration temperature (approximately C) and recording temperature ( C). The location of the lower oesophageal sphincter (LES) was determined manometrically for each patient following a -h fast prior to the start of period. The ph catheter was inserted nasogastrically with the proximal probe cm above the upper border of the LES and the distal ph probe positioned in the stomach cm below the proximal electrode, approximately min prior to initiating ph recording. Ambulatory, continuous -h gastric ph monitoring was conducted in each period while patients were restricted to bed in a recumbent position (about ) from : h on day, until : hours the following day. Pharmacokinetic assessments Omeprazole pharmacokinetics were assessed in the subset of patients who received IR-OME in period and esomeprazole in period. Blood samples for the assessment of plasma omeprazole levels were drawn following administration of trial drug at : hours on day at,,,,, 9,,,, and min ( h) post-dose. In addition, a baseline sample was obtained from each patient within min prior to dosing. Plasma omeprazole was measured using a validated liquid chromatography/mass spectrometry assay. Pharmacokinetic (PK) parameters assessed in this trial included peak plasma omeprazole concentration (C max ) and time to peak plasma concentration (T max ) obtained directly from the data without interpolation, and area under the omeprazole plasma concentration curve from time zero to time t after dosing [AUC( t)]. The AUC( t) was calculated using the trapezoidal rule, for the entire h of the night-time period. Mean plasma concentrations at each sampling time were also calculated. Analysis populations Assuming NAB rates of % after treatment with IR- OME and % after treatment with either lansoprazole or esomeprazole, evaluable patients were required

4 P. O. KATZ et al. to provide 9% power to detect a difference in NAB rates between IR-OME mg and the two comparators at the a ¼. level of significance. Further, assuming that the ph recordings for up to 9 patients (%) were either not available or not technically satisfactory for statistical analysis, patients were enrolled. Patients who withdrew or were discontinued from the study were not replaced. The safety population consisted of all patients who received at least one dose of a study drug. The PD population included all patients who completed all three treatment periods for all three study drugs with technically satisfactory ph recordings. The determination of evaluable patients was based on a blinded assessment of ph data. The PK population consisted of those patients who received IR-OME in period and esomeprazole in period. Calculation of pharmacodynamic parameters All gastric ph values outside the acceptable range of.., inclusive, were excluded prior to calculating PD parameters. An occurrence of NAB was determined using all available -s values in the -h interval from : to : hours. If the gastric ph was < for more than 9 consecutive, nonmissing values (> h), the patient was classified as having had an occurrence of NAB. When calculating the percentage of time with gastric ph > and median gastric ph, the ph recording for each patient was divided into -min intervals. If ph values were missing in an interval, only the available values were used for the calculations. If all ph values were missing in an interval, the mean (median) of the values from the intervals that immediately preceded and immediately followed it were used to calculate the percentage of time with gastric ph > (median gastric ph) for that interval. The percentage of time with gastric ph > and median gastric ph was calculated for each patient as the mean (percentage of time) or median (median ph) of the values in each -min interval. IGA was calculated as specified by Gardner et al. Pharmacodynamic analyses All PD analyses with the exception of the evaluation of IGA were prospectively defined prior to study initiation. The percentage of patients experiencing NAB during the -h night-time interval and the percentage of patients with gastric ph > for hourly increments between : and : hours were compared for IR-OME and esomeprazole, and for IR-OME and lansoprazole, using the McNemar s test. The percentage of time with gastric ph > and median gastric ph were compared for IR-OME and esomeprazole, and for IR-OME and lansoprazole, using the Wilcoxon signed rank test. RESULTS Demographics and baseline characteristics for the patients enrolled are displayed in Table. Data from two patients were excluded from the PD analyses because of malfunctioning of gastric ph probes during one of the three treatment periods. Three patients were prematurely withdrawn from the study: one patient had a positive pregnancy test and two patients withdrew consent for personal reasons. Of the 9 patients included in the PD analyses,.% were H. pylori negative. All patients were fully compliant with the dosing regimen in all three treatment periods. Nocturnal acid breakthrough After days of once daily bedtime dosing, significantly fewer patients experienced NAB during the -h night-time interval after treatment with IR-OME mg than after treatment with esomeprazole mg Table. Demographics and baseline characteristics Baseline characteristics Total patients (n ¼ ) Sex (%) Female. Male. Race/ethnicity (%) Caucasian. Black. Hispanic. Other. Age (years) Median. Range 9 Weight (kg) Median. Range.. The denominator for calculating percentages was the patients who received at least one dose of a trial drug.

5 CONTROL OF NOCTURNAL GASTRIC ACIDITY IN PATIENTS WITH NIGHT-TIME HEARTBURN Table. Summary of gastric acidity after bedtime administration of IR-OME mg, lansoprazole mg and esomeprazole mg on day Night-time intervals Treatment pharmacodynamic endpoint : : hours First half of the night : : hours : : hours Entire night-time period : : hours IR-OME mg Per cent of patients with NAB Per cent time gastric ph >. (. 9.).9 (..). (..). (. 9.) Median gastric ph. (..). (..). (..). (..) Lansoprazole mg Per cent of patients with NAB.* 9.* 9.* 9.* Per cent time gastric ph >. (..). (..). (..9). (..) Median gastric ph. (..9). (..). (..).9 (..) Esomeprazole mg Per cent of patients with NAB.*.* 9.* 9.* Percent time gastric ph >. (..). (..). (9..).9 (..) Median gastric ph. (..9). (.9.9).9 (..9). (..) The pharmacodynamic endpoints were calculated for each of the patients who completed all three treatments with technically acceptable ph recordings (n ¼ 9). Table entries for percentage of time with gastric ph > and median gastric ph present the medians (th and th percentiles) of these by-patient values. NAB ¼ gastric ph < continuously for more than h during night-time. * P-value <. when compared with IR-OME using the McNemar s test. P-value <. when compared with IR-OME using the Wilcoxon signed rank test. or lansoprazole mg (Table ). Of the 9 evaluable patients, (%) experienced NAB after treatment with IR-OME mg; in contrast, patients (9%) experienced NAB after treatment with either lansoprazole mg or esomeprazole mg (P <., both comparisons). Night-time gastric acidity Plots of median gastric ph during the night show that after bedtime dosing with IR-OME, median gastric ph rapidly increased above within the first min after administration (Figure ). In contrast, after treatment with esomeprazole, median gastric ph did not increase to above until : hours, approximately h after dosing. After treatment with lansoprazole, median gastric ph did not increase to above until : hours, more than h after dosing. During the first half of the night (: : hours) IR-OME provided significantly faster and greater gastric acid control than treatment with either delayed-release formulation (Table ). The percentage of time with gastric ph > and median gastric ph (Figure ) were both significantly higher after treatment with IR-OME (.9% and., respectively) than after treatment with either lansoprazole (.% and.) or esomeprazole (.% and.) (P <., all comparisons). Correspondingly, the percentage of patients with median gastric ph > after treatment with IR-OME was significantly higher during the first half of the night, than after treatment with either lansoprazole or esomeprazole (Table ). Over the entire night-time period (: : hours), the percentage of time with gastric ph > and median gastric ph after treatment with IR- OME (.% and., respectively) were significantly higher than after treatment with lansoprazole (.% and.) (P <., both comparisons). Gastric acid control over the -h night-time period was comparable for IR-OME and esomeprazole (Table ). Control of night-time gastric acidity was also assessed in terms of IGA, calculated for -h intervals during the night (Figure ). During the first half of the night, median IGA was numerically lower for each -h interval after treatment with IR-OME than after treatment with either lansoprazole or esomeprazole.

6 P. O. KATZ et al. Gastric ph IR-OME mg : : : : : : : : : Time (-h clock) Gastric ph Lansoprazole mg : : : : : : : : : Time (-h clock) Gastric ph Esomeprazole mg : : : : : : : : : Time (-h clock) Figure. Median gastric ph during the night on day. Note: Each point represents the median ph during the -min interval. Median Gastric ph.. Median Gastric ph.. IR-OME mg Lansoprazole mg IR-OME mg Esomeprazole mg Figure. Median gastric ph during the first half of the night on day. Note: Median gastric ph during the first half of the night (: : hours) was calculated for each patient; solid lines connect the treatment values for each patient. The dashed lines represent the medians for each treatment group (IR-OME vs. lansoprazole and IR-OME vs. esomeprazole; P <., both comparisons). Table. Percentage of patients with median gastric ph > following bedtime dosing on day Night-time intervals Treatment : : hours : : hours : : hours : : hours IR-OME mg Lansoprazole mg.*.*.*.* Esomeprazole mg.*... * P value <. when compared with IR-OME using the McNemar s test. P value <. when compared with IR-OME using the McNemar s test. Twenty-four hour gastric acidity The percentage of time with gastric ph > for the - h period was.% after treatment with IR-OME vs. 9% with esomeprazole (P <.) and.% with lansoprazole (P <., when compared with both IR-OME and esomeprazole). Similarly, the median - h gastric ph after treatment with IR-OME was. vs.. with esomeprazole (P <.) and. with lansoprazole (P <., when compared with both IR-OME and esomeprazole). Omeprazole pharmacokinetics Omeprazole PK parameters for IR-OME and esomeprazole are summarized in Table and plots of mean

7 CONTROL OF NOCTURNAL GASTRIC ACIDITY IN PATIENTS WITH NIGHT-TIME HEARTBURN Integrated gastric acidity (mmol*h/ml) Dose IR-OME Lansoprazole Esomeprazole : : : : : : : : : Time (-h clock) Plasma omeprazole concentration (ng/ml) IR-OME mg Esomeprazole mg : : : : : : : : : Time (-h clock) Figure. Integrated gastric acidity for one-hour intervals during the night on day. plasma omeprazole levels at each sampling time are presented in Figure. These results show that IR- OME was absorbed significantly faster than esomeprazole; within min after administration of IR-OME, mean plasma omeprazole levels rose to ng/ml, or % of C max, which was reached in min. In contrast, a minimal increase in plasma omeprazole levels was observed within the first min after administration of esomeprazole, and a comparable plasma omeprazole level of ng/ml was not achieved until h after dosing. Peak plasma levels after treatment with esomeprazole were reached more than h after dosing. Safety and tolerability Each study drug was well tolerated. No serious adverse events were reported over the course of the study. A Figure. Mean (SD) plasma omeprazole concentrations following bedtime dosing of IR-OME mg and esomeprazole mg on day. Note: The curve for esomeprazole was shifted to the right (by min) to avoid overlap of the error bars (SD). Results are from the patients who received IR-OME in period and esomeprazole in period. total of adverse events were considered by the investigator at least possibly related to treatment ( with IR-OME, with lansoprazole and with esomeprazole), and there were no notable differences between the events reported for the different treatments. No clinically significant changes were observed by physical examination or laboratory assessment. DISCUSSION The results of this study demonstrate that dosing IR- OME once daily at bedtime provides rapid and sustained control of nocturnal gastric acidity. IR-OME Table. Serum omeprazole pharmacokinetic parameters after bedtime dosing of IR-OME mg and esomeprazole mg on day IR-OME mg Esomeprazole mg Parameter* n Arithmetic mean S.D. n Arithmetic mean S.D. C max (ng ml ) ) 9.. T max (h).... AUC( t) (ngh ml ) ) 9 kel ( h ) ).... T/ (h).... Values for C max and AUC were rounded to four significant digits and T max, T/ and kel were rounded to two decimal places after summary statistics were calculated. Blood samples were collected over h post-dose. Results are from patients who received IR-OME in period and esomeprazole in period.

8 P. O. KATZ et al. was superior to both lansoprazole and esomeprazole in reducing the occurrence of NAB as defined in this study. Additionally, IR-OME was superior to lansoprazole in reducing gastric acidity throughout the night as assessed by the percentage of time with gastric ph >, median gastric ph and IGA. Although esomeprazole was equally effective as IR-OME in reducing gastric acidity over the entire -h night-time period, the onset of action of IR-OME was significantly faster than that of esomeprazole. This delay in onset of the PD effect of esomeprazole is best explained by differences in the PK profiles of these two compounds. In this study, IR-OME was clearly superior to lansoprazole and esomeprazole in controlling gastric acidity during the first half of the night. Administration of IR-OME at bedtime produced a rapid rise in gastric ph, which was not observed with either lansoprazole or esomeprazole. This rapid onset of action is likely because of the combination of immediate neutralization of gastric acid by the antacid buffer, and the fast absorption of omeprazole, as clinically significant plasma levels of omeprazole were achieved within min after dosing. Physiologically, acid output peaks in the late evening to early night-time hours, resulting in maximum gastric acidity between approximately : and : hours, followed by a substantial decrease in acid secretion between : and : h. This potentially vulnerable period appears to be the most likely time for reflux to occur as suggested by a recent study in which the majority of pathological reflux episodes were found to occur during the first half of the sleeping period. These observations highlight the potential relevance of assessing and reducing gastric acidity during the early portion of the sleeping period and the potential role of IR-OME in preventing night-time GERD. Thus, taking an immediate-release PPI at bedtime might provide an advantage by controlling gastric ph in the early part of the night when control of gastric acidity seems most critical. In clinical practice, PPIs are commonly given before the first meal of the day. Unfortunately, with this regimen, overnight recovery of gastric acidity is almost universal such that nocturnal reflux may occur., Acid recovery at night may be responsible for the fact that approximately % of patients with erosive oesophagitis and approximately % of patients with heartburn empirically treated with a PPI once daily continue to experience nocturnal heartburn., Taking a delayed-release PPI before the evening meal or splitting the dose (before breakfast and before dinner) both improve night-time ph control compared with AM dosing. However, nocturnal recovery of gastric acid secretion still occurs, usually between and AM. To control nocturnal gastric acidity in these patients, adding an HRA at bedtime has been recommended. However, this strategy adds an additional drug at bedtime, and many patients develop tolerance to HRAs. Administering IR-OME at bedtime instead of a PPI in the morning and an HRA at bedtime would be a simpler and likely more effective alternative for patients who require nocturnal acid control. Patients with Barrett s oesophagus frequently reflux in the overnight period, despite twice daily dosing. Although aggressive oesophageal acid control has yet to be proved to change the natural history of the disease, many advocate aggressive acid control in these patients. As twice daily dosing with delayed-release PPIs will fail to normalize oesophageal acid exposure in % of Barrett s patients, administration of IR-OME at bedtime is worthy of study in these patients. As substantial plasma levels of omeprazole are detected within min after administration of IR-OME, our findings suggest that patients who require more rapid and effective nocturnal gastric acid control might benefit from an immediate-release PPI that could be taken at bedtime, either regularly or on demand, without the need for meal-induced activation of proton pumps. While the slow onset of action of esomeprazole is consistent with its delayed-release formulation, its overall control of nocturnal gastric acidity was unexpected, because there was no mealinduced activation of proton pumps. The relatively poor overnight control of gastric ph by lansoprazole, which required more than h to reach the threshold of gastric ph >, is more consistent with what one would expect when delayed-release PPIs are taken before bed on an empty stomach. The reason for the dramatic difference in the performance of the delayedrelease PPIs is unclear. In summary, administration of IR-OME at bedtime resulted in a substantial reduction in NAB compared with esomeprazole and lansoprazole, and provided significantly faster control of night-time ph than the other two products. Eight hours night-time acid control with IR-OME was superior to that with lansoprazole and comparable to that with esomeprazole. This study and a previously published study comparing control of nocturnal acidity with IR-OME and pantoprazole both suggest that bedtime dosing with IR-OME

9 CONTROL OF NOCTURNAL GASTRIC ACIDITY IN PATIENTS WITH NIGHT-TIME HEARTBURN may be an effective strategy for managing patients with night-time heartburn. Declaration of funding interest: This study was funded in full by Santarus Inc. ACKNOWLEDGEMENT Authors declaration of personal interests: Philip O. Katz has served as a Consultant for Santarus Inc. REFERENCES Hila A, Castell DO. Nighttime reflux is primarily an early event. J Clin Gastroenterology ; 9: 9. Moore JG, Englert E Jr. Circadian rhythm of gastric acid secretion in man. Nature 9; :. Prewett EJ, Smith JT, Nwokolo CU, et al. Twenty-four hour intragastric acidity and plasma gastric concentration profiles in female and male subjects. Clin Sci (Lond) 99; : 9. Miehlke S, Madisch A, Kirsch C, et al. Intragastric acidity during treatment with esomeprazole mg twice daily or pantoprazole mg twice daily a randomized, two-way crossover study. Aliment Pharmacol Ther ; : 9. Tutuian R, Castell DO. Nocturnal acid breakthrough approach to management. Med Gen Med ; :. Locke GR III, Talley NJ, Fett SL, et al. Prevalence and clinical spectrum of gastroesophageal reflux: a populationbased study in Olmsted County, Minnesota. Gastroenterology 99; :. Gallup Organization. A Gallup Survey of Heartburn Across America. Princeton, NJ: Gallup Organization, 99. Shaker R, Castell D, Schoenfeld P, et al. Nighttime heartburn is an underappreciated clinical problem that impacts sleep and daytime function: results of a Gallup survey conducted on behalf of the American Gastroenterological Association. Am J Gastroenterol ; 9: 9. 9 Farup C, Kleinman L, Sloan S, et al. The impact of nocturnal symptoms associated with gastroesophageal reflux disease on health-related quality of life. Arch Intern Med ; :. Katz PO, Hatlebakk JG, Castell DO. Gastric acidity and acid breakthrough with twice-daily omeprazole or lansoprazole. Aliment Pharmacol Ther ; : 9. Castell D, Bagin R, Goldlust B, et al. Comparison of the effects of immediaterelease omeprazole powder for oral suspension and pantoprazole delayedrelease tablets on nocturnal acid breakthrough in patients with symptomatic gastroesophageal reflux disease. Aliment Pharmacol Ther ; :. Pandolfino JE, Schreiner MA, Lee TJ, et al. Comparison of the Bravo wireless and Digitrapper catheter-based ph monitoring systems for measuring esophageal acid exposure. Am J Gastroenterol ; :. Peghini PL, Katz PO, Bracy NA, et al. Nocturnal recovery of gastric acid secretion with twice daily dosing of proton pump inhibitors. Am J Gastroenterol 99; 9:. Gardner JD, Rodriguez-Stanley S, Robinson M. Integrated acidity and the pathophysiology of gastroesophageal reflux disease. Am J Gastroenterol ; 9:. Katz PO, Anderson C, Khoury R, et al. Gastro-oesophageal reflux associated with nocturnal gastric acid breakthrough on proton pump inhibitors. Aliment Pharmacol Ther 99; :. Tutuian R, Katz P, Castell D. A PPI is a PPI is a PPI: Lessons from prolonged intragastric ph monitoring (Abstract). Gastroenterology ; : A. Castell DO, Kahrilas PJ, Richter JE, et al. Esomeprazole ( mg) compared with lansoprazole ( mg) in the treatment of erosive esophagitis. Am J Gastroenterol ; 9:. Chey W, Huang B, Jackson RL. Lansoprazole and esomeprazole in symptomatic GERD: a double-blind, randomised, multicentre trial in patients confirms comparable symptom relief. Clin Drug Invest ; : 9.