Morning dose or twice-daily proton pump inhibitor (PPI) use is often prescribed to heal severe reflux esophagitis.
Compare the effect of single dose morning (control arm) versus nighttime (experimental arm) omeprazole/sodium bicarbonate (Zegerid®) (IR-OME) on esophagitis and gastroesophageal reflux symptoms.
Adult outpatients with Los Angeles grade C or D esophagitis were allocated to open-label 40 mg IR-OME once a day for 8 weeks in a prospective, randomized, parallel design, single center study. Esophagogastroduodenoscopy (EGD) and validated self-report symptom questionnaires were completed at baseline and follow-up. Intention-to-treat and per-protocol analyses were performed.
Ninety-two of 128 (72 %) eligible subjects participated [64 (70 %) male, mean age 58 (range 19–86), median BMI 29 (range 21–51), 58 C:34 D]. Overall, 81 (88 %) subjects healed [n = 70 (76 %)] or improved [n = 11 (12 %)] erosions. There was no significant difference (morning vs. night) in mucosal healing [81 vs. 71 %, (p = 0.44)] or symptom resolution [heartburn (77 vs. 65 %, p = 0.12), acid regurgitation (82 vs. 73 %, p = 0.28)]. Prevalence of newly identified Barrett’s esophagus was 14 % with half diagnosed only after treatment.
Once-daily IR-OME (taken morning or night) effectively heals severe reflux esophagitis and improves GERD symptoms. Results support the clinical practice recommendation to repeat EGD after 8 weeks PPI therapy in severe esophagitis patients to assure healing and exclude Barrett’s esophagus.
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Body mass index
Gastroesophageal reflux disease
Histamine receptor antagonist
Intestinal metaplasia of the cardia
Los Angeles classification system for erosive reflux esophagitis
Long segment Barrett’s esophagus
Mayo Dysphagia Questionnaire–30 day
Proton pump inhibitor
Short segment Barrett’s esophagus
Lundell LR, Dent J, Bennett JR, et al. Endoscopic assessment of oesophagitis: clinical and functional correlates and further validation of the Los Angeles classification. Gut. 1999;45:172–180.
Chiba N, De Gara CJ, Wilkinson JM, Hunt RH. Speed of healing and symptom relief in grade II to IV gastroesophageal reflux disease: a meta-analysis. Gastroenterology. 1997;112:1798–1810.
Richter JE, Kahrilas PJ, Johanson J, et al. Efficacy and safety of esomeprazole compared with omeprazole in GERD patients with erosive esophagitis: a randomized controlled trial. Am J Gastroenterol. 2001;96:656–665.
Labenz J, Armstrong D, Lauritsen K, et al. A randomized comparative study of esomeprazole 40 mg versus pantoprazole 40 mg for healing erosive oesophagitis: the expo study. Aliment Pharmacol Ther. 2005;21:739–746.
Kinoshita Y, Hongo M. Efficacy of twice-daily rabeprazole for reflux esophagitis patients refractory to standard once-daily administration of PPI: the Japan-based TWICE Study. Am J Gastroenterol. 2012;107:522–530.
Adachi K, Fujishiro H, Katsube T, et al. Predominant nocturnal acid reflux in patients with los angeles grade c and d reflux esophagitis. J Gastroenterol Hepatol. 2001;16:1191–1196.
Campos GR, Peters JH, DeMeester TR, Öberg S, Crookes PF, Mason RJ. The pattern of esophageal acid exposure in gastroesophageal reflux disease influences the severity of the disease. Arch Surg. 1999;134:882–888.
Orr WC, Allen ML, Robinson M. The pattern of nocturnal and diurnal esophageal acid exposure in the pathogenesis of erosive mucosal damage. Am J Gastroenterol. 1994;89:509–512.
Frazzoni M, De Micheli E, Savarino V. Different patterns of oesophageal acid exposure distinguish complicated reflux disease from either erosive reflux oesophagitis or non-erosive reflux disease. Aliment Pharmacol Ther. 2003;18:1091–1098.
Bredenoord AJ. Mechanisms of reflux perception in gastroesophageal reflux disease: a review. Am J Gastroenterol. 2012;107:8–15.
Peura DA, Pilmer B, Hunt B, Mody R, Perez MC. The effects of increasing body mass index on heartburn severity, frequency and response to treatment with dexlansoprazole or lansoprazole. Aliment Pharmacol Ther. 2013;37:810–818.
Peghini PL, Katz PO, Castell DO. Ranitidine controls nocturnal gastric acid breakthrough on omeprazole: a controlled study in normal subjects. Gastroenterology. 1998;115:1335–1339.
Cicala M, Emerenziani S, Guarino MP, Ribolsi M. Proton pump inhibitor resistance, the real challenge in gastro-esophageal reflux disease. World J Gastroenterol. 2013;19:6529–6535.
Castell D, Bagin R, Goldlust B, Major J, Hepburn B. Comparison of the effects of immediate-release omeprazole powder for oral suspension and pantoprazole delayed-release tablets on nocturnal acid breakthrough in patients with symptomatic gastro-oesophageal reflux disease. Aliment Pharmacol Ther. 2005;21:1467–1474.
Katz PO, Koch FK, Ballard ED, et al. Comparison of the effects of immediate-release omeprazole oral suspension, delayed-release lansoprazole capsules and delayed-release esomeprazole capsules on nocturnal gastric acidity after bedtime dosing in patients with night-time gerd symptoms. Aliment Pharmacol Ther. 2007;25:197–205.
Castell D. Review of immediate-release omeprazole for the treatment of gastric acid-related disorders. Expert Opin Pharmacother. 2005;6:2501–2510.
Moher D, Hopewell S, Schulz KF, et al. Consort 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. J Clin Epidemiol. 2010;63:e1–37.
McElhiney J, Lohse MR, Arora AS, et al. The mayo dysphagia questionnaire-30: documentation of reliability and validity of a tool for interventional trials in adults with esophageal disease. Dysphagia. 2010;25:221–230.
Sharma P, Dent J, Armstrong D, et al. The development and validation of an endoscopic grading system for Barrett’s esophagus: the Prague C & M criteria. Gastroenterology. 2006;131:1392–1399.
Lee D, Lee KJ, Kim KM, Lim SK. Prevalence of asymptomatic erosive esophagitis and factors associated with symptom presentation of erosive esophagitis. Scand J Gastroenterol. 2013;48:906–912.
Hanna S, Rastogi A, Weston AP, et al. Detection of Barrett’s esophagus after endoscopic healing of erosive esophagitis. Am J Gastroenterol. 2006;101:1416–1420.
Modiano N, Gerson LB. Risk factors for the detection of Barrett’s esophagus in patients with erosive esophagitis. Gastrointest Endosc. 2009;69:1014–1020.
Rodriguez S, Mattek N, Lieberman D, Fennerty B, Eisen G. Barrett’s esophagus on repeat endoscopy: should we look more than once? Am J Gastroenterol. 2008;103:1892–1897.
Gilani N, Gerkin RD, Ramirez FC, Hakim S, Randolph AC. Prevalence of Barrett’s esophagus in patients with moderate to severe erosive esophagitis. World J Gastroenterol. 2008;14:3518–3522.
Gaddam S, Maddur H, Wani S, et al. Risk factors for nocturnal reflux in a large GERD cohort. J Clin Gastroenterol. 2011;45:764–768.
Chiba H, Gunji T, Sato H, et al. A cross-sectional study on the risk factors for erosive esophagitis in young adults. Intern Med. 2012;51:1293–1299.
Egan LJ, Myhre GM, Mays DC, Dierkhising RA, Kammer PP, Murray JA. Cyp2c19 pharmacogenetics in the clinical use of proton-pump inhibitors for gastro-oesophageal reflux disease: variant alleles predict gastric acid suppression, but not oesophageal acid exposure or reflux symptoms. Aliment Pharmacol Ther. 2003;17:1521–1528.
Abdalla AA, Petersen BT, Ott BJ, et al. Impact of feedback and didactic sessions on the reporting behavior of upper endoscopic findings by physicians and nurses. Clin Gastroenterol Hepatol. 2007;5:326–330.
We thank Lori R. Anderson for help typing and submitting the manuscript; Kaiser Lim, M.D., Prasad Iyer, M.D., Adil A. Abdalla, M.B.B.S. and Judith McElhiney, M.D., for help recruiting subjects; Rayna M. Grothe, M.D., Joanna M. Peloquin, M.D., Shabana F. Pasha, M.D., and Darlene E. Graner, CCC-SLP, for help conceptualizing the study design; and Michael D. Van Norstrand, M.D., Ph.D., for editorial assistance. The project was supported in part by the Miles and Shirley Fiterman Center for Digestive Diseases at Mayo Clinic, Rochester, Minnesota. Yvonne Romero, M.D., was supported in part by a grant from the National Institutes of Health (NIDDK 02956) and the Robert Wood Johnson Foundation Harold Amos Medical Faculty Development Program.
Conflict of interest
This study was funded in part by an Investigator-Initiated Research Award from Santarus, Inc., IRB # 07-008503. Santarus Inc. provided study medications [omeprazole/sodium bicarbonate (Zegerid®) and Gelusil™] at no charge. No assistance for manuscript preparation was received from Santarus, Inc. Unpaid academicians voluntarily wrote this paper. All data analysis was undertaken by Felicity T. Enders, Diana M. Orbelo, Nancy N. Diehl, Debra M. Geno, Yvonne Romero, David A. Katzka, Dawn L. Francis, Michael D. Crowell, Sami R. Achem, Ramona DeJesus, Vikneswaran Namasivayam, Steven C. Adamson, Amindra S. Arora, Andrew J. Majka, Jeffrey A. Alexander, Joseph A. Murray, Kee Wook Jung, Margaret S. Houston and Angela O’Neil, all of whom are or were Mayo Clinic employees at the time. Santarus Inc. provided salary support to FTE, NND, and DMG for data analysis, and DMG and MF for data collection. The Santarus study sponsors, William F. Bleker, M.D., Philip Yeung, Pharm.D., Gregg Checani, M.D., and E. David Ballard, M.D., participated in study design but did not participate in data collection, analysis or interpretation, and did not participate in drafting the manuscript or in the decision to publish the results of this trial. Study sponsors were permitted to review the manuscript prior to its submission for publication. Yvonne Romero has received research funding from Aptalis, AstraZeneca, Meritage Pharma and Takeda, has served as an ad hoc consultant for Kala, and receives royalties from the licensed use of the Mayo Dysphagia Questionnaire—30 day. Dawn L. Francis has received research funding from AstraZeneca, and receives royalties from the licensed use of the Mayo Dysphagia Questionnaire—30 day. Jeffrey A. Alexander has received research funding from Aptalis and Merck, serves as a consultant and has stock holdings of Meritage Pharma and receives royalties from the licensed use of the Mayo Dysphagia Questionnaire—30 day. Joseph A. Murray has an ownership interest with Torax Medical Inc. and Vysera Biomedical, and receives royalties from the licensed use of the Mayo Dysphagia Questionnaire—30 day. Felicity T. Enders, Michael D. Crowell, Debra M. Geno, Matthew Lohse, Nancy N. Diehl, and Mary Fredericksen receive royalties from the licensed use of the Mayo Dysphagia Questionnaire—30 day.
ClinicalTrials.gov, Number: NCT00693225.
Hypotheses and aims
A priori hypotheses:
The timing of administration of omeprazole/sodium bicarbonate will impact its efficacy in healing esophagitis
Nighttime administration (experimental arm) will be superior in healing esophagitis compared to morning administration (control arm) prior to a meal.
A priori primary aim: quantify the efficacy of omeprazole/sodium bicarbonate in healing severe erosive esophagitis when used either as a morning or before bedtime dose.
A priori secondary aims:
Determine the percent of patients who improve, but did not resolve, their mucosal damage.
Determine the efficacy of omeprazole/sodium bicarbonate on symptom resolution in patients with erosive esophagitis
Assess the frequency with which a diagnosis of Barrett’s esophagus was made once the overlying severe esophagitis had healed.
A priori exploratory and hypothesis-generating objective: assess objective control of esophageal acid exposure as determined by ambulatory pH monitoring.
IR-OME powder instruction details
Omeprazole/sodium bicarbonate powder for oral suspension 40 mg was supplied in individual packets that are emptied into a small cup containing 15–30 ml (1–2 tablespoons) of water, one per day, for 8 weeks. They were asked to stir well and drink immediately then refill the cup with water and drink. Subjects assigned to morning dosing were instructed to take the medication on an empty stomach, immediately upon rising, 20–60 min prior to chewing a solid. Subjects assigned to nighttime dosing were instructed to keep the medication by their bedside; taking the medication in a standing or seated upright position immediately before turning off the lights with the intention to sleep. The subject was instructed to not use other liquids or foods for 20 min after taking their study medication for those allocated to morning dosing, and until the next morning for those allocated to nighttime dosing.
LA classification system 
LA grade A: one or more erosions on non-confluent folds in which the longest erosion is <5 mm length
LA grade B: one or more erosions on non-confluent folds in which the longest erosion is ≥5 mm length
LA grade C: confluent erosions of more than one fold involving <75 % of the circumference.
LA grade D: confluent erosions involving ≥75 % of the circumference of the distal esophagus.
The endoscopic evaluation results were grouped for outcomes analysis as follows, for subjects with:
LA C esophagitis at baseline:
Healed = no erosions in the esophagus
Improved = LA grades A or B
Same or worse = C or D at follow-up
LA D esophagitis at baseline:
Healed = no erosions in the esophagus
Improved = LA grades A, B or C
Same = LA grade D at follow-up
MDQ-30 scoring details
Symptom analysis: GERD symptoms (absent, infrequent, frequent) at baseline and follow-up were measured by the MDQ-30.
Frequent: The respondent reports experiencing heartburn, (a burning pain or discomfort behind the breast bone in the chest), at least once per week, with at least one of the following: heartburn that improves with antacids, awakens them at night, or radiates to the neck. Respondents would also be categorized as having frequent GERD symptoms if they report experiencing acid regurgitation, (a bitter or sour-tasting fluid coming up from the stomach into the mouth or throat), at least once per week.
Absent: The respondent is completely asymptomatic; denies experiencing heartburn or acid regurgitation.
Infrequent: Any heartburn or acid regurgitation in those who do not meet criteria for frequent symptoms.
Symptom outcomes at follow-up include:
Complete resolution (subjects with either frequent or infrequent GERD symptoms at baseline report the absence of GERD symptoms at follow-up)
Partial resolution (subjects with frequent GERD symptoms at baseline meet criteria for infrequent GERD symptoms at follow-up)
No improvement (subjects with either frequent or infrequent GERD symptoms at baseline continue to report those symptoms at follow-up)
Per-protocol demographic results (Table 5)
Table 6 is an ITT (worst case) version of Table 2. Table 6 was not used in the body of the manuscript because there was imbalance in the subjects who completed their questionnaires. Nine subjects allocated to nighttime IR-OME dosing, compared to 3 subjects allocated to morning dosing did not fully complete their follow-up questionnaires. In the ITT analysis, we assume subjects without follow-up questionnaire information have severe symptoms at follow-up. Thus, the statistically significant findings shown in Table 6 are artifactual. Thus, we opted to show the Per-protocol results in the manuscript (see Table 2).
Detailed demographic information of 13 subjects ultimately diagnosed with Barrett’s esophagus (Table 8).
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Orbelo, D.M., Enders, F.T., Romero, Y. et al. Once-Daily Omeprazole/Sodium Bicarbonate Heals Severe Refractory Reflux Esophagitis with Morning or Nighttime Dosing. Dig Dis Sci 60, 146–162 (2015). https://doi.org/10.1007/s10620-013-3017-y