Dig Dis Sci DOI 10.1007/s10620-013-3017-y

ORIGINAL ARTICLE

Once-Daily Omeprazole/Sodium Bicarbonate Heals Severe Refractory Reflux Esophagitis with Morning or Nighttime Dosing Diana M. Orbelo • Felicity T. Enders • Yvonne Romero • Dawn L. Francis • Sami R. Achem • Tushar S. Dabade • Michael D. Crowell • Debra M. Geno • Ramona S. DeJesus • Vikneswaran Namasivayam • Steven C. Adamson • Amindra S. Arora • Andrew J. Majka • Jeffrey A. Alexander • Joseph A. Murray Matthew Lohse • Nancy N. Diehl • Mary Fredericksen • Kee Wook Jung • Margaret S. Houston • Angela E. O’Neil • David A. Katzka

•

Received: 5 July 2013 / Accepted: 27 December 2013  Springer Science+Business Media New York 2014

Abstract Background Morning dose or twice-daily proton pump inhibitor (PPI) use is often prescribed to heal severe reflux esophagitis. Aim 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. Methods 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

ClinicalTrials.gov, Number: NCT00693225.

were completed at baseline and follow-up. Intention-to-treat and per-protocol analyses were performed. Results 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. Conclusions 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

D. M. Orbelo (&) Department of Otolaryngology, Mayo Clinic, 200 First St., SW, Rochester, MN 55905, USA e-mail: [email protected]

J. A. Murray e-mail: [email protected]

F. T. Enders Division of Biomedical Statistics and Informatics, Mayo Clinic, 200 First St., SW, Rochester, MN 55905, USA e-mail: [email protected]

D. A. Katzka e-mail: [email protected]

Y. Romero
D. M. Geno
A. S. Arora
J. A. Alexander
J. A. Murray
M. Fredericksen
D. A. Katzka Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First St., SW, Rochester, MN 55905, USA e-mail: [email protected] D. M. Geno e-mail: [email protected] A. S. Arora e-mail: [email protected]

M. Fredericksen e-mail: [email protected]

D. L. Francis
S. R. Achem Division of Gastroenterology and Hepatology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA e-mail: [email protected] S. R. Achem e-mail: [email protected] T. S. Dabade Department of Dermatology, Tufts Medical Center, 1615 Tremont St., Boston, MA 02120, USA

J. A. Alexander e-mail: [email protected]

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therapy in severe esophagitis patients to assure healing and exclude Barrett’s esophagus. Keywords Gastroesophageal reflux disease
Esophagitis
Barrett’s esophagus
Prospective randomized controlled trial Abbreviations BE Barrett’s esophagus BMI Body mass index EGD Esophagogastroduodenoscopy GERD Gastroesophageal reflux disease HH Hiatal hernia HRA Histamine receptor antagonist IMC Intestinal metaplasia of the cardia IR-OME Immediate release-omeprazole ITT Intention-to-treat analysis LA Los Angeles classification system for erosive reflux esophagitis LSBE Long segment Barrett’s esophagus MDQ-30 Mayo Dysphagia Questionnaire–30 day PPI Proton pump inhibitor SSBE Short segment Barrett’s esophagus

Introduction Severe gastroesophageal reflux disease (GERD) can lead to gross esophageal epithelial injury [1]. While the advent of proton pump inhibitors (PPIs) has revolutionized the ability to heal erosive esophagitis, as many as 10–40 % of patients

with severe Los Angeles (LA) grade C or D erosive esophagitis do not heal after 8 weeks of PPI therapy [2–5]. Among reasons cited for sub-optimal healing is poor control of nocturnal acid exposure [6–9] due to reduced esophageal clearance from hypotensive peristalsis, reduction of swallowing during sleep, loss of normal upright gravitational factors that enhance esophageal clearance [10], obesity [11], and insufficient effect of PPI’s on nocturnal acid secretion [12]. Pharmacological attempts to control nocturnal esophageal acid reflux have been difficult. Reasons for this include the standard recommendation to take their PPI upon arising in the morning. Inherent to this standard is an adherence burden, specifically the need to swallow their PPI immediately upon awakening, waiting 20–60 min prior to masticating a solid. Arguably, this is less burdensome than trying to remember to take a PPI dose on an empty stomach prior to the last meal of the day; a recommendation that is often added when twice-daily PPIs are empirically prescribed for those with severe, LA Grade C or D, erosive esophagitis [13]. A newer formulation of omeprazole (Zegerid), which combines omeprazole with sodium bicarbonate in lieu of an enteric coating, is the only immediate-release PPI; with demonstrated ability to control gastric pH when administered at bedtime, in the absence of a meal [14, 15]. It has been theorized that the rapid elevation of gastric pH with sodium bicarbonate taken before bedtime may be a sufficient stimulus to release gastrin and activate proton pumps, facilitating pump binding without the need for food stimulus [16]. Thus, our a priori hypotheses are that the timing of administration of immediate release omeprazole sodium bicarbonate (IR-OME) will impact its efficacy in healing

M. D. Crowell Division of Gastroenterology and Hepatology, Mayo Clinic, 13400 E. Shea Blvd., Scottsdale, AZ 85259, USA e-mail: [email protected]

M. Lohse Department of Surgery, Virginia Mason Medical Center, 901 8th Ave., Seattle, WA 98104, USA e-mail: [email protected]

R. S. DeJesus Division of Primary Care Internal Medicine, Mayo Clinic, 200 First St., SW, Rochester, MN 55905, USA e-mail: [email protected]

N. N. Diehl Division of Biostatistics, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA e-mail: [email protected]

V. Namasivayam Department of Gastroenterology and Hepatology, Singapore General Hospital, Outram Road, Singapore 169608, Singapore e-mail: [email protected]

K. W. Jung Department of Internal Medicine, Asan Medical Center, Seoul, Korea e-mail: [email protected]

S. C. Adamson Department of Family Medicine, Lake City Medical Center, Mayo Clinic Health System, 500 W. Grant St., Lake City, MN 55041, USA e-mail: [email protected]

M. S. Houston
A. E. O’Neil Department of Family Medicine, Mayo Clinic, 200 First St., SW, Rochester, MN 55905, USA e-mail: [email protected]

A. J. Majka Division of General Internal Medicine, Mayo Clinic, 200 First St., SW, Rochester, MN 55905, USA e-mail: [email protected]

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A. E. O’Neil e-mail: [email protected]

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esophagitis and that convienient once-daily administration at nighttime, immediately prior to sleep, (experimental arm) will be superior in healing esophagitis compared to morning administration 20–60 min prior to a meal (control arm). For a full list of a priori and post hoc aims, see ‘‘Appendix’’.

Methods The study and manuscript adhere to the 2010 CONSORT Statement for parallel group randomized trials [17]. The Mayo Clinic Institutional Review Board approved the study on March 18, 2008. Trial registration: Clinical Trials.gov Identifier: NCT00693225.

bleeding diathesis, neoplasm of the esophagus or stomach, previous upper GI surgery [esophagectomy, Heller myotomy, hiatal hernia (HH) repair], diabetic gastroparesis, esophageal motility disorder, Zollinger-Ellison syndrome, infection with human immunodeficiency virus, history of gastric or small bowel obstruction, reported an inability to read due to blindness, cognitive dysfunction or English language illiteracy, diagnosis of a disorder which predisposes to unreliable responses such as Schizophrenia or dementia. Pregnant and lactating females, children younger than 18, and vulnerable populations were excluded. Those with primary residence outside the USA or in prison, and anyone opting out of research activities at the Mayo Clinic, were excluded. Interventions

Trial Design A single center, randomized, open-label, parallel-group pilot study was conducted. Subjects were randomly allocated to receive daily study medication, either in the morning or at night, for 8 weeks. No changes in trial design were needed [17]. Participants Target population: Adults with severe (LA grade C or D) erosive reflux esophagitis seen at an academic center in Rochester, Minnesota, that provides both primary and specialty care. Study accural occurred from June 20, 2008, to May 24, 2010. All patients underwent a clinically indicated esophagogastroduodenoscopy (EGD) as advised by their primary health care provider. Those meeting inclusion and exclusion criteria were then invited to participate. Eligibility Criteria Inclusion Criteria Subjects were age 18 years or older. Patients with reflux esophagitis despite use of a non-omeprazole PPI(s) or histamine receptor antagonist (HRAs) were invited to discontinue their PPI and/or HRAs and participate without a wash-out period. Exclusion Criteria Patients were excluded if they were already using some formulation of omeprazole when diagnosed with esophagitis or reported intolerance or previously failed omeprazole. Patients were excluded if they were using clopidogrel (Plavix), or had one or more of the following diagnoses:

All subjects received a one-on-one educational session, developed for a 6th grade reading level, describing the normal physiology of the upper gastrointestinal tract, the pathophysiology of HH and reflux esophagitis, food stuffs that contribute to reflux, and lifestyle modifications they can take to limit reflux prior to their invitation to participate in the trial as per our standard clinical care. IR-OME powder for oral suspension 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 per standardized instructions. Instructions to subjects allocated to the experimental nighttime arm specified that they keep the medication by their bedside; take it in a standing or seated upright position immediately before turning off the lights with the intention to sleep and not to use any food until the next morning. See ‘‘Appendix’’ for complete instruction details. GelusilTM use was recorded and distributed as an ‘‘on demand’’ rescue antacid (dried aluminum hydroxide gel 200 mg, magnesium hydroxide 200 mg, simethicone 25 mg); no more than 12 tablets in a 24-h period, as directed on the box. All other antacids, HRAs, PPIs and sucralfate were prohibited. No other medication was altered. Study coordinators conducted a structured phone interview at 3 weeks to: (1) clarify the start date of the study medicine, (2) assure medication tolerance, (3) review the proper medication administration, including clarifying dose time in relationship to meals, (4) review concomitant medications, and (5) inquire about adverse events. After 8 weeks, follow-up EGD was performed by a clinical (not research) endoscopist who was blind to the study and subject allocation. The Mayo Dysphagia Questionnaire–30 Day (MDQ-30) [18] was administered at baseline and after 8 weeks of study medication. Chart review was performed by a reviewer blind to endoscopic

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Assessed for eligibility (n=387)

Excluded (n=295) ♦ Did not meet inclusion criteria (n=259) Already on omeprazole Previously failed omeprazole Intolerant of PPI therapy Age < 18 Bleeding diathesis Clopidogrel use Diabetic gastroparesis Esophageal varices Gastric/small bowel obstruction Morbid obesity Motility disorder Multiple medical issues Neoplasm of esophagus or stomach Pacemaker/defibrillator Previous GI surgery Provider would not permit contact Residence outside the US/prison Significant memory loss

Randomized (n=92)

♦ Declined ♦

= 64 = 21 = 1 = 4 = 7 = 2 = 1 = 3 = 13 = 1 = 28 = 33 = 13 = 2 = 42 = 19 = 2 = 3

to participate (n=18)

Other reasons (n=18) - Could not reach = 1 - Not planning to return to MN = 17

Allocated to morning dose (n=43) ♦ Received allocated intervention (n=43)

Allocated to bedtime dose (n=49) ♦ Received allocated intervention (n=48)

♦

♦

Did not receive allocated intervention (n=0)

Did not receive allocated intervention (n=1) Changed mind soon after randomization

Lost to follow-up (n=1) Did not return to Rochester

Lost to follow-up (n=2) Did not return to Rochester

Discontinued intervention (n=1) Perceived side effect

Discontinued intervention (n=3) Perceived side effect

N = 80

N = 80

Fig. 1 Flow diagram of the progress through the phases of a parallel-randomized trial of two groups (morning vs. nighttime dosing)

results and outcomes to categorize baseline symptoms in four subjects who did not complete the MDQ-30. Subjects were invited to undergo a pH study while on IR-OME during the final week of the study while using study medication. Those with persistent erosions at follow-up EGD were offered twice-daily dosing IR-OME for an additional 8 weeks as a courtesy. Remuneration was

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offered to each participant only after consent had been gained to avoid the appearance of coercion. Outcomes Measured Endoscopic outcome measures included the presence and degree of esophageal erosions. Results were categorized

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based on initial severity, LA grade C or D, and level of improvement at follow-up: healed, improved, or same or worse. See ‘‘Appendix’’ for endoscopic outcomes details. GERD symptoms were measured as frequent, infrequent or absent. Symptom outcomes were categorised into three groups: complete resolution, partial resolution, and no improvement. See ‘‘Appendix’’ for MDQ-30 scoring details. Additional outcomes measures included Barrett’s esophagus (BE) defined by 1 cm or greater length salmoncolored mucosa in the tubular esophagus at EGD with histologic confirmation of intestinal metaplasia with goblet cells, most severe degree of dysplasia, and presence and length of HH. Long segment BE (LSBE) is C3 cm length, while short segment BE (SSBE) ranges from 1 to 3 cm in length. Intestinal metaplasia of the cardia (IMC) is defined as salmon-colored mucosa in the esophagus shorter than 1 cm in length demonstrating intestinal metaplasia with goblet cells at histology. The 24-h pH test outcomes included total, upright, and supine time with pH \ 4 %. Body Mass Index (BMI) (kg/m2), sex (m/f), and date of birth were collected. Primary and secondary outcomes were pre-specified and unaltered per CONSORT guidelines [17]. Sample Size Our clinical a priori estimate was that 70 % of subjects would heal their esophagitis with daily morning IR-OME, while 90 % would heal taking IR-OME at night. Resources were available to test 100 subjects and, assuming 50 subjects were randomized to each arm (for a total of 100 subjects), we would have 74 % power to detect a 20 % difference in the timing of the doses. Although large numbers of subjects met criteria for LA C or D esophagitis, the majority were inpatients with at least one exclusion criteria and, hence, not eligible to participate. See Fig. 1. Due to slow accrual, this study was stopped early at n = 92, resulting in 71 % power to detect a 20 % difference in esophageal healing between morning and nighttime dosing. Randomization and Masking Study medication was allocated in a 1:1 ratio (morning vs. nighttime) using stratification (in blocks of 6) to balance: (1) sex, (2) current use of a PPI (yes/no), and (3) severity of esophagitis (C/D). The Mayo Clinic Research Pharmacy generated the random allocation sequence and assigned participants to intervention. After obtaining permission from their primary care provider, study coordinators contacted the patient. Patients who gave permission then

Table 1 Subject demographics at baseline, intention-to-treat analysis Factor

Morning dosing n = 43

Nighttime dosing n = 49

p value

Male sex [n (%)]

30 (70)

34 (69)

1.00

Age [years median (range)]

59 (19–86)

58 (26–86)

0.92

BMI [kg/m2 median (range)]

29.4 (24.5–51.1)

30.1 (21.2–47.8)

0.98

Hiatal hernia (HH) Overall [n (%)]

36 (84)

40 (83)

1.00

Of those with HH [cm average (range)]

3.9 (1–13)

3.4 (1–6)

0.25

LA grade C

26 (60)

32 (65)

0.67

LA grade D

17 (40)

17 (35)

Esophagitis severity [n (%)]

Using a PPI at time of baseline EGD [n (%)] Overall 12 (28) 15 (31)

0.82

Among asymptomatic subjects

3 of 9 (33)

3 of 7 (43)

1.00

Among symptomatic GERD subjects

9 of 34 (26)

12 of 42 (29)

1.00

Using a H2 blocker and or OTC antacid at time of baseline EGD [n (%)] Overall

31 (74)

32 (70)

1.00

p values from Fisher’s exact test for categorical variables and the Wilcoxon rank sum test for continuous variables

underwent review of their medical records to assure eligibility before undergoing randomization. Blinding Subjects, study coordinators, and Research Pharmacy personnel were aware of treatment assignment (morning vs. nighttime dosing). Subjects were encouraged to report their use of ‘‘once-daily omeprazole/sodium bicarbonate’’ only if an inquiry was made by a health care provider (and to not volunteer further detail such as the time of day of administration), to maintain blinding. Managing clinicians, endoscopists, investigators, and the biostatistical team remained blinded to treatment time until the analysis was complete. Over 14,000 EGDs are conducted annually by 58 individual endoscopists facilitating blinding. Statistical Methods An intention-to-treat (ITT) analysis was performed in which subjects with missing follow-up symptom data were presumed to have frequent symptoms, and missing EGD data were presumed to have severe LA D esophagitis. Additionally, a sensitivity analysis assuming the

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Dig Dis Sci LA Grades C & D Morning v. Nighttime Dosing of Omeprazole/Sodium Bicarbonate

Healing of Severe Erosive Reflux Esophagitis

Intention-To-Treat

LA C

LA D

p = 0.44

p = 0.19

p = 1.0

Percent %

Overall

Morning Nighttime Morning Nighttime Morning Nighttime Total

N = 43

Healed

N = 49

N=26

Improved

N = 22

Same or Worse

N = 17

N = 17

No EGD at follow-up

Fig. 2 Endoscopic outcomes following 8 weeks of omeprazole/ sodium bicarbonate once a day in subjects with LA grade C or D erosive esophagitis: morning versus nighttime dosing. Intention-totreat

best-case scenario was completed. A per-protocol analysis was also performed. Categorical variables are summarized as proportions. Fisher’s exact test was used to compare categorical variables between groups. Ordinal logistic regression was used to adjust the association between esophageal healing and time of dosing for baseline symptom frequency. For the exploratory aim assessing the association between nocturnal acid exposure in subjects who healed versus those with persistent esophagitis, statistical analysis was not performed due to limited sample size.

Results Ninety-two of 128 (72 %) eligible patients provided written informed consent to participate (Fig. 1) and were used in the ITT analysis (Table 1). Of these, 43 were randomized to morning and 49 to nighttime dosing (due to randomization based on blocks of 6). There were no significant group differences in sex, age, BMI, esophagitis grade, presence or length of HH, or prestudy PPI use (Table 1). Eight subjects dropped out by: changing their mind prior to receiving study medication (n = 1), not returning for follow-up (n = 3), or stopping study medication due to perceived side effect (n = 4). Eighty subjects underwent baseline and follow-up EGD and entirely completed all questionnaires, and thus were used in the per-protocol analysis (Table 5 in the Appendix).

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Overall 81 of 92 (88 %) subjects healed [n = 70 (76 %)] or improved [n = 11 (12 %)] their severe reflux esophagitis following treatment with IR-OME once per day for 8 weeks. Figure 2 shows the ITT frequency of healing in all subjects, and in subgroups with either LA C or D esophagitis, comparing results between morning versus nighttime dosing. There was no statistically significant difference in healing for the morning group compared to the nighttime group (81 vs. 71 %, p = 0.44) or for subjects with LA C versus D esophagitis (78 vs. 74 %, p = 0.80). Lack of healing was not associated with elevated BMI (p = 0.48). When comparing healing rates between the small subset of subjects with severe esophagitis while on a non-omeprazole PPI at baseline versus the majority of subject who were PPI naive at baseline, there was no statistically significant difference in healing (74 vs. 77 %, p = 0.79). GelusilTM use was reported in 23 of 43 (53 %) subjects allocated to the morning group (mean 10 capsules over an 8-week period, range 1–75 capsules); and in 30 of 49 (61 %) subjects allocated to the nighttime group (mean 16 capsules over 8 weeks, range 2–100 capsules) (p = 0.22). GERD Symptoms at Baseline and Follow-up Table 2 shows the per-protocol distribution of heartburn, acid regurgitation, and overall GERD symptoms for subjects allocated to morning versus nighttime dosing. ITT results are shown in the Appendix (Table 6). At baseline, when scored independently, heartburn and acid regurgitation were reported equally. However, when the overall GERD symptom score was calculated, subjects allocated to the morning dose met criteria for frequent GERD more often than subjects allocated to nighttime dosing (68 vs. 50 %, p = 0.02). Overall, there was no statistically significant difference in symptom response comparing morning versus nighttime dosing after adjusting for baseline symptom frequency. Both dose strategies demonstrated efficacy in resolving symptoms [heartburn (77 vs. 65 %, p = 0.12), acid regurgitation (82 vs. 73 %, p = 0.28), and GERD (73 vs. 60 %, p = 0.14)]. At baseline, 16 of 92 (17 %) subjects with severe esophagitis were asymptomatic, denying heartburn and acid regurgitation, while 6 of 16 (38 %) were using a PPI at the time of diagnosis. Another 23 (25 %) had infrequent symptoms. Only 53 (58 %) subjects with severe esophagitis had frequent (at least weekly) symptoms at baseline. Figure 3a, b shows per protocol heartburn and acid regurgitation symptoms at baseline and after 8 weeks of IR-OME for each individual participant. The ITT results (in which missing data are analyzed assuming a worst case

Dig Dis Sci Table 2 Frequency of heartburn, acid regurgitation, and overall GERD symptoms in subjects allocated to morning (n = 40) versus nighttime (n = 40) dosing of omeprazole/sodium bicarbonate at entry and following 8 weeks therapy, per-protocol analysis Symptom

Time of study drug administration

pc

Symptom frequency At baseline Absent n (%)

Heartburn Acid regurgitation GERD

After 8 weeks therapy

Infrequent n (%)

Freq. n (%)

p

0.24

Morning dose

11 (28)

5 (12)

24 (60)

Nighttime dose

8 (20)

11 (27)

21 (53)

Morning dose

19 (47)

11 (28)

10 (25)

Nighttime dose

17 (42)

17 (43)

6 (15)

4 (10)

27 (68)

15 (38)

20 (50)

Morning dose Nighttime dose

9 (22) 5 (12)

a

0.31 0.02

Absent n (%)

Infrequent n (%)

Freq. n (%)

pb

31 (77)

7 (18)

2 (5)

0.31

0.12

26 (65)

8 (20)

6 (15)

33 (82)

4 (10)

3 (8)

0.63

0.28

29 (73)

7 (18)

4 (10)

29 (73)

7 (17)

4 (10)

0.51

0.14

24 (60)

9 (23)

7 (17)

a

p values from Fisher’s exact test comparing symptom frequency (absent, infrequent or frequent) for patients with morning and nighttime doses

b

p values from Fisher’s exact test comparing symptom frequency (absent, infrequent or frequent) for patients with morning and nighttime doses

c

Using ordinal logistic regression, this p value assesses whether time of dose is associated with symptom frequency at 8 weeks, after adjusting for baseline symptom frequency

scenario) are depicted in Fig. 4a, b in the Appendix, while sensitivity analyses (in which estimates include best case scenarios) are presented in the Appendix (Table 7; Fig. 5a, b). Notably, the outcome did not meaningfully change with per protocol versus ITT analysis. Overall, 76 subjects with severe esophagitis reported GERD symptoms at baseline. Although the majority healed their esophagitis at follow-up [57 of 76 (75 %)] and reported complete symptom resolution [35 of 57 (61 %)], 22 of 57 (39 %) reported persistent reflux symptoms despite demonstrating complete mucosal healing. Five of 19 (26 %) subjects who reported GERD symptoms at baseline but who did not heal at follow-up became asymptomatic despite demonstrating persistent mucosal injury. In contrast, 16 (17 %) subjects denied heartburn and acid regurgitation at baseline, despite having severe esophagitis. Endoscopy was done to investigate dysphagia and chest pain. Thirteen of 16 (81 %) subjects healed of whom 12 (92 %) remained asymptomatic. Prevalence of BE, Intestinal Metaplasia of the Cardia, and HH in Patients with Severe Reflux Esophagitis at Baseline None of the subjects in this study were known to have BE prior to undergoing a clinically indicated EGD; at which time severe reflux esophagitis was diagnosed thus, prompting their recruitment into this study. At baseline, 6 subjects were diagnosed with prevalent BE and esophagitis (LA C = 5, LA D = 1). Table 3 shows the initial extent of BE as measured using Prague criteria [19] and the degree and extent of the erosions, if described. For subjects simultaneously diagnosed with both BE and esophagitis during the baseline EGD, the length of the Barrett’s

segment did not change after the esophagitis had healed as the erosions were located at the proximally displaced aspect of the Barrett’s segment at the squamocolumnar junction. At follow-up EGD, once the esophagitis had healed, 7 additional subjects were diagnosed with BE for the first time, the majority [5 of 7 (71 %)] of whom had LA D esophagitis at baseline. Overall, 13 of 92 (14 %) subjects [7 (54 %) males, median age 58 years (range 30–77), median BMI 29.1 (range 24.6–51)] with severe esophagitis had concomitant BE. In over half (54 %) of the cases, the diagnosis of BE would have been missed had a post-PPI research follow-up EGD not been done, including three subjects with C5 cm segment lengths. Detailed demographics including HH length at baseline EGD are shown in Table 8 in the Appendix. Overall, 7 of 58 (12 %) LA C and 6 of 34 (18 %) LA D subjects had BE. After healing the esophagitis, 2 additional subjects met criteria for IMC (1 male, both age 55, BMIs of 30.8 and 33.4). One subject with SSBE had indefinite dysplasia. No subject had low- or high-grade dysplasia, or cancer. All BE subjects [n = 13 (100 %)] had a HH [mean length 5 cm (95 % CI 3–7); see Appendix Table 8 for specifics] while HH was diagnosed in 64 of 79 (81 %) non-BE subjects [mean length 3 cm (95 % CI 3–4)] (p = 0.15). Effect of IR-OME on Esophageal Acid Exposure Nineteen subjects underwent 24-h pH testing. Seven subjects inadvertently discontinued the study medication prior to placement of the pH probe and were excluded from this a priori exploratory subgroup analysis. Table 4 shows the results of the 12 subjects who underwent pH testing while on study medication (n = 6 morning, n = 6 night). There

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Dig Dis Sci Fig. 3 a Frequency of heartburn before and after 8 weeks of omeprazole/sodium bicarbonate therapy comparing morning versus nighttime dosing. Per protocol. b Frequency of acid regurgitation before and after 8 weeks of omeprazole/sodium bicarbonate therapy comparing morning versus nighttime dosing. Per protocol

(a)

Heartburn Per-Protocol

Morning vs Nighttime: Before and After Treatment with Omeprazole/Sodium Bicarbonate

Morning Dose

Nighttime Dose

Frequent

Infrequent

Absent

Before

(b)

After

Before

After

Acid Regurgitation Per-Protocol

Morning vs Nighttime: Before and After Treatment with Omeprazole/Sodium Bicarbonate

Morning Dose

Nighttime Dose

Frequent

Infrequent

Absent

Before

was 100 % healing with the morning dose (6/6) and 83 % healing with the nighttime dose (5/6). None of the 6 subjects taking morning IR-OME had abnormal total esophageal acid exposure (based on % duration of pH \ 4 of 4 % or greater), and only 1/6 had abnormal nocturnal acid exposure at 5.7 % time pH \ 4. Three of 6 subjects using IR-OME at night demonstrated both abnormal total and nocturnal acid exposure; with one subject demonstrating 16.1 % time pH \ 4 when supine. Safety and Tolerability Discontinuation resulting from adverse events occurred in 1 subject allocated to morning dosing (joint and muscle pain) and three subjects allocated to nighttime dosing (peripheral edema and/or increased blood pressure).

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After

Before

After

Common PPI side effects (headache, nausea, abdominal pain, and diarrhea) were not reported.

Discussion Given the difficulty of healing severe erosive reflux esophagitis, this study adds several important points to the literature: (1) once-daily IR-OME is highly effective in healing LA grades C and D esophagitis; (2) our data do not support the hypothesis that nighttime administration of IROME is superior in healing esophagitis compared to morning IR-OME administration but do provide the basis on which to calculate the sample size for a future equivalency study; (3) among subjects with esophagitis who perceive heartburn and/or acid regurgitation at baseline,

Dig Dis Sci Table 3 Endoscopic features of subjects ultimately diagnosed with Barrett’s esophagus EGD at which BE was diagnosed

Baseline

Follow-up

Subject ID

Baseline LA grade

Extent of erosions (cm)

Baseline EGD

Follow-up EGD

Prague criteria

Prague criteria

C

M

C

LSBE vs. SSBE

M

104

C

15

15

15

15

15

LSBE

183

C

14

14

14

a

a

LSBE

163 187

C C

11 3

9 3

11 3

7 2

10 3

LSBE LSBE

190

C

2

0

2

0

2

SSBE

182

D

8

0

2

0

2

SSBE

185

D

4

6

6

LSBE

164

C

ND

5

6

LSBE

131

C

ND

4

5

LSBE

109

D

3

2

2

SSBE

103

D

1

2

2

SSBE

110

D

5

0

2

SSBE

149

D

ND

0

2

SSBE

Rows 1–4 and 7–9 indicate morning (control group) and rows 5, 6 and 10–13 indicate nighttime (experimental group) C circumferential extent of Barrett’s esophagus mucosa per the Prague Classification System, LSBE long segment Barrett’s esophagus, M maximal extent of Barrett’s esophagus mucosa per the Prague Classification System, ND not described, SSBE short segment Barrett’s esophagus a

Lost to follow-up

Table 4 pH test results among subjects who permitted testing while on omeprazole/sodium bicarbonate once daily, either in the morning or at nighttime Time of dose

Morning omeprazole/sodium bicarbonate users

Subject no.

Esophagitis severity Pre-

Post-

1

C

Healed

3

D

Healed

5 9a

C C

10 11

Abnormal post-treatment pH test?

Total

Upright

No

3.3

0

5.7

No

1.9

3.3

0.6

Healed Healed

No No

0.8 0.3

1.1

0.5

b

b

D

Healed

No

2

2.7

0

D

Healed

No

1

1.7

0

1.5

1.5

2.7

Mean % time pH \ 4 for morning users Nighttime omeprazole/sodium bicarbonate users

Wireless pH catheter used

b

Information not available

Supine

2

D

Healed

No

1.9

3.1

0

4

C

Healed

No

0.8

1.6

0

6

C

Healed

Yes

6.6

0

16.1

7

C

Healed

No

0

0

0

8

D

Healed

Yes

10.8

15.7

2.9

12

C

B

Yes

11.5

11.3

12

5.7

5.3

3.6

Mean % time pH \ 4 for nighttime users a

% time pH \ 4

morning and nighttime administration of IR-OME are equally likely to resolve their symptoms; (4) the absence or presence of esophageal symptoms may not predict the

presence of severe esophagitis nor predict its resolution; and (5) there was no association between elevated BMI and failure to heal esophagitis [11].

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Dig Dis Sci

The complete healing rate (76 %) found in this study compares to 60–90 % of subjects with LA grade C or D erosive esophagitis depending on PPI type and dose in the literature [2–5]. It has been hypothesized that lack of efficacy of PPIs might be explained by poor control of nocturnal acid secretion. Pharmacologic therapies for severe esophagitis have included twice-daily-administered PPIs, sometimes in combination with nighttime HRAs. In this study, once-daily IR-OME achieved complete healing in 76 % of subjects with severe erosive esophagitis, with improvement in another 12 %. As a result, nearly all subjects in this study had improvement in endoscopic appearance. Notably, these favorable results were as robust in subjects with grade D esophagitis as those with grade C. It is important to highlight that our team could not control for the various types, dose, duration, or adherence to pre-study PPI prior to their baseline EGD. Therefore, the high effectiveness of once-daily dosing must be taken in the context of the study. Specifically, upon enrollment, study participants were provided with structured education and counseling regarding how their PPI should be taken and had close follow-up while taking the study medication. This may help explain the high healing rates as well as the finding that those previously prescribed a non-omeprazole PPI healed at the same rate as those who were PPI naı¨ve. It is also noteworthy that this level of improvement was achieved with both morning and nighttime administration of IR-OME. This was surprising, as it was hypothesized that better control of nocturnal gastric acid secretion with nighttime administration would be more effective in healing esophagitis. On the other hand, our 24-h pH data, though limited, demonstrated at least equal, if not better, control of both day and nighttime esophageal acid exposure with morning administration of IR-OME. These results could provide a valuable practical and theoretical economic advantage to the patient by allowing the single use of IROME in either the morning or nighttime to heal their severe erosive esophagitis, without the need for twice-daily PPI dosing or supplementation with an HRA. The efficacy of once-daily administration may also lead to improved patient adherence, especially in patients with minimal symptoms. At the time of their diagnosis with severe esophagitis, 83 % of subjects reported perception of GERD symptoms, and when healed, 61 % reported symptom resolution. For 39 %, however, despite healing, their symptoms persisted. This observation is consistent with the concept that acid suppression medications alter the pH of the refluxate but they do not alter the mechanics of reflux. Our findings that 17 % reported no reflux symptoms despite severe esophagitis differs from those of others. Specifically, Lee et al. [20] found that 43 % with erosive esophagitis did not report symptoms. This difference may be due to quality

123

and focus of GERD questionnaires or differences in severity of reflux esophagitis. The limited reliability of self-reported GERD symptoms to predict the presence or healing of esophagitis further reinforces the need for endoscopic evaluation of chronic GERD patients before and after medical therapy. Retrospective studies have estimated that 9–27 % of patients with severe esophagitis have concomitant BE [21– 24]. In this prospective study, 12 % LA C and 18 % LA D subjects met stringent criteria for long- and short-segment BE (demonstrating intestinal metaplasia with goblet cells at histology). An additional 2 % (2/92) subjects had IMC. To limit the likelihood of over-diagnosing a condition with elevated neoplastic risk, namely BE, it is our group’s standardized clinical practice to not biopsy salmon-colored mucosa unless it is at least 1 cm in length. Thus, we may have under-diagnosed the frequency of IMC and ultrashort BE in this cohort (that was endoscoped in a clinical endoscopy suite by 1 of 58 endoscopists). This clinical practice, however, strengthens the reliability of the BE prevalence calculations. Unlike retrospective analyses, the prevalent BE values in this prospective study were not overinflated by including subjects with IMC who were misclassified as having SSBE. Most subjects simultaneously diagnosed with BE and esophagitis during the baseline EGD had obvious long-segment BE and LA C erosions at the proximal aspect of the BE segment. Once the esophagitis healed, the measured BE segment length generally remained the same (not longer). It did not appear that the erosions were hiding additional salmon-colored mucosa beneath them. Conversely, most of the subjects in whom BE was only appreciated once the esophagitis had healed initially had LA D esophagitis, in which the erosions involved more than 75 % of the circumference of the esophagus. The diagnosis of BE would have been missed in 54 % of BE patients had a post-PPI research follow-up EGD not been done, including three subjects with C5 cm segment lengths. Some have informally postulated that the extent of a Barrett’s segment is due to the proximal extent of each patient’s individual esophagitis or refluxate. Proximal extent of reflux was not measured in this study, but, given the length of erosions at baseline, shown in Table 3, it appears that this prospective study has demonstrated that the extent of a subject’s erosions does not strongly correlate with and often underestimates the BE length (measured when the esophagitis has healed). This study supports the role for HH in advanced esophageal inflammatory disease. HH is an independent risk factor for nocturnal reflux and erosive esophagitis [25, 26]. Therefore, it is not surprising that 81 % of non-BE and 100 % of BE subjects with concomitant severe esophagitis in our study have a HH.

Dig Dis Sci

Several weaknesses to this study should be considered. Firstly, our methods relied upon pill counting as a proxy for adherence to medical therapy. Thus, unrecognized medication adherence issues may explain the failure to achieve mucosal healing in some subjects. Conversely, adherence may have been better than real-world situations due to careful education of subjects and close follow-up. Other factors may also be involved in non-healing such as hypermetabolizer CYP2C19 genotype status [27] or greater degrees of reflux in some subjects. In this open-label study, subjects were not blind as to when they took their medication. Limited resources to conduct the study made employment of a double dummy design unfeasible. Also, one of the benefits of participating in this study, from the subject’s perspective, was the opportunity to avoid twicedaily dosing to heal their severe erosive esophagitis. Secondly, despite implementation of stratification for treatment allocation, symptom frequencies were not equally distributed between the two groups at baseline and, by chance, subjects allocated to morning dosing met criteria for overall GERD symptoms statistically more often than did their counterparts allocated to nighttime dosing. Also, there was an imbalance that occurred among the subjects who completed their follow-up questionnaires; this resulted in our reliance on the per-protocol analysis to assess the impact of dose timing on symptom response (Fig. 3a, b). Nine subjects allocated to nighttime IR-OME dosing compared to three subjects allocated to morning dosing, did not fully complete their follow-up questionnaires. The ITT analysis assumption is that subjects missing follow-up questionnaire information have severe symptoms, hence the statistically significant findings shown in the ITT analysis (Fig. 4a, b) in the Appendix are deemed artifactual and not clinically relevant. Figures 5a, b in the Appendix show the sensitivity analysis, in which missing data are assumed to reflect complete lack of GERD symptoms and healing of esophageal injury (i.e. the best case scenario). Because more patients in the nighttime dosing group were missing follow-up data, the sensitivity analyses produced statistically significant results only for the worst case scenario ITT results. Thirdly, now that PPIs are available over-the-counter, the frequency that outpatients present de novo with LA C and D esophagitis is probably low. In this study, although 387 consecutive patients were found to have LA C or D esophagitis over a 23-month period of time, the majority were inpatients with at least one exclusion criteria. The subjects in this study were medically stable outpatients. In order to attain 80 % power to detect the difference we observed for esophageal healing between morning and nighttime dosing, a total of 610 subjects would be needed. Finally, the results of this project are not generalizable to patients using an omeprazole product at the time of their diagnosis with severe esophagitis.

On the other hand, this study has several strengths. Most importantly, this was a prospective randomized trial exclusively for LA grades C and D erosive esophagitis in a relatively large cohort. Endoscopists judging the primary outcome of esophageal mucosal status (normal vs. esophagitis) were not aware that the subject was enrolled in a clinical trial; hence, they were blind, as were the statistician and remainder of the investigative team. This large academic endoscopic group has previously demonstrated near-perfect incorporation and use of the Los Angeles grading system in the past [28]. This study is generalizable to patients found to have severe reflux esophagitis despite being prescribed (or self-prescribed) non-omeprazole PPI therapy. In conclusion, our study demonstrates the high efficacy of single dose IR-OME administered either in the morning or at night for healing or improving severe erosive esophagitis. It lays a foundation for consideration of equivalency studies comparing morning versus evening PPI treatment as well as comparison of once-daily versus twice-daily PPI administration to heal severe erosive esophagitis. The aim of this study was to compare conventional morning PPI dosing that requires a higher burden of adherence to convenient nighttime dosing. Had the experimental arm of taking the PPI at nighttime proven superior, it could have potentially increased adherence to PPI treatment and greatly improved our ability to heal erosive reflux esophagitis. Unfortunately, that did not work. At this time, adherence is still required for optimal benefit. Also, although symptom correlation to healing can be demonstrated in a majority of subjects, in a sizable number of subjects, symptom profiles do not reliably predict esophageal healing with therapy. Therefore, clinicians should continue evaluating these patients by objective means, specifically endoscopy, to ensure endoscopic healing and to allow for accurate assessment for the presence of BE after pharmacologic therapy; especially in patients with LA D esophagitis. Acknowledgments 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 GelusilTM] at no charge. No

123

Dig Dis Sci 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.

•

•

2.

• 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: • •

123

IR-OME powder instruction details

Endoscopic outcomes LA classification system [1]

Appendix

•

A priori exploratory and hypothesis-generating objective: assess objective control of esophageal acid exposure as determined by ambulatory pH monitoring.

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. 3.

1.

Assess the frequency with which a diagnosis of Barrett’s esophagus was made once the overlying severe esophagitis had healed.

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

• • •

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 C5 mm length LA grade C: confluent erosions of more than one fold involving \75 % of the circumference. LA grade D: confluent erosions involving C75 % 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: • • •

•

LA D esophagitis at baseline: • • •

4.

Healed = no erosions in the esophagus Improved = LA grades A or B Same or worse = C or D at follow-up

Healed = no erosions in the esophagus Improved = LA grades A, B or C Same = LA grade D at follow-up

MDQ-30 scoring details

Dig Dis Sci

•

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

Table 5 Subject demographics at baseline, per-protocol analysis Factor

Morning dosing n = 40

Nighttime dosing n = 40

p value

•

Male sex [n (%)]

28 (70)

28 (70)

1.00

•

Age [years median (range)]

59 (19–86)

61 (30–86)

0.61

BMI [kg/m2 median (range)]

29.9 (24.5–51.1)

29.9 (21.2–45.6)

0.58

•

Hiatal hernia (HH)

Symptom outcomes at follow-up include:

Overall [n (%)]

34 (85)

33 (83)

1.00

Of those with HH [cm average (range)]

4.0 (1–13)

3.3 (1–6)

0.27

LA grade C

24 (60)

26 (65)

0.82

•

LA grade D

16 (40)

14 (35)

•

•

Esophagitis severity [n (%)]

Using a PPI at time of baseline EGD [n (%)] Overall

12 (30)

10 (25)

0.80

Among asymptomatic subjects

3 of 9 (33)

2 of 5 (40)

1.00

Among symptomatic GERD subjects

9 of 31 (26)

8 of 35 (29)

0.59

5. 6.

Using a H2 blocker and or OTC antacid at time of baseline EGD [n (%)] Overall 29 (73) 29 (73) 1.00 p values from Fisher’s exact test for categorical variables and the Wilcoxon rank sum test for continuous variables

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 sourtasting 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.

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 followup)

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

Table 6 Frequency of heartburn, acid regurgitation and overall GERD symptoms in subjects allocated to morning (n = 43) versus nighttime (n = 49) dosing of omeprazole/sodium bicarbonate at entry and following 8 weeks therapy, intention-to-treat analysis (worst case) Symptom

Time of study drug administration

pc

Symptom frequency At baseline Absent n (%)

Heartburn

Infrequent n (%)

After 8 weeks therapy Freq. n (%)

pa

0.26

Morning dose

11 (26)

6 (14)

26 (60)

Nighttime dose

10 (20)

14 (29)

25 (51)

Acid regurgitation

Morning dose

21 (49)

11 (26)

11 (26)

GERD

Nighttime dose Morning dose

20 (41) 9 (21)

21 (43) 5 (12)

8 (16) 29 (67)

Nighttime dose

7 (14)

18 (37)

24 (49)

a

Absent n (%)

Infrequent n (%)

Freq. n (%)

31 (72)

7 (16)

5 (12)

26 (53)

8 (16)

15 (31)

0.19

33 (77)

4 (9)

0.02

29 (59) 29 (67)

7 (14) 7 (16)

24 (49)

9 (18)

16 (33)

pb

0.09

0.03

6 (14)

0.21

0.06

13 (27) 7 (16)

0.15

0.04

p values from Fisher’s exact test comparing symptom frequency (absent, infrequent or frequent) for patients with morning and nighttime doses

b

p values from Fisher’s exact test comparing symptom frequency (absent, infrequent or frequent) for patients with morning and nighttime doses. For this ITT analysis, missing values were presumed to have frequent symptoms

c Using ordinal logistic regression, this p value assesses whether time of dose is associated with symptom frequency at eight weeks, after adjusting for baseline symptom frequency. For this ITT analysis, missing values at follow-up were presumed to have frequent symptoms

123

Dig Dis Sci Table 7 Frequency of heartburn, acid regurgitation and overall GERD symptoms in subjects allocated to morning (n = 43) versus nighttime (n = 49) dosing of omeprazole/sodium bicarbonate at entry and following 8 weeks therapy, Intention-To-Treat analysis (best case) Symptom

Time of study drug administration

pc

Symptom frequency At baseline Absent n (%)

Heartburn Acid regurgitation GERD a

After 8 weeks therapy

Infrequent n (%)

a

Freq. n (%)

p

0.26

Morning dose

11 (26)

6 (14)

26 (60)

Nighttime dose

10 (20)

14 (29)

25 (51)

Morning dose

21 (49)

11 (26)

11 (26)

Nighttime dose

20 (41)

21 (43)

8 (16)

Morning dose

9 (21)

5 (12)

29 (67)

Nighttime dose

7 (14)

18 (37)

24 (49)

0.19 0.02

Absent n (%)

Infrequent n (%)

Freq. n (%)

pb

34 (79)

7 (16)

2 (5)

0.46

0.25

35 (79)

8 (16)

6 (12) 0.79

0.47

36 (84)

4 (9)

3 (7)

38 (78)

7 (14)

4 (8)

32 (74)

7 (16)

4 (9)

33 (67)

9 (18)

7 (14)

0.76

023

p values from Fisher’s exact test comparing symptom frequency (absent, infrequent or frequent) for patients with morning and nighttime doses

b

p values from Fisher’s exact test comparing symptom frequency (absent, infrequent or frequent) for patients with morning and nighttime doses. For this ITT analysis, missing values were presumed to have absent symptoms

c

Using ordinal logistic regression, this p value assesses whether time of dose is associated with symptom frequency at 8 weeks, after adjusting for baseline symptom frequency. For this ITT analysis, missing values at follow-up were presumed to have absent symptoms

Table 8 Endoscopic features of subjects ultimately diagnosed with Barrett’s esophagus showing raw symptom, sex, age and Body Mass Index (BMI) data EGD at which BE was diagnosed

Baseline

Follow-up

Study ID

Baseline LA grade

Extent of erosions (cm)

Baseline EGD

Follow-up EGD

Prague criteria

Prague criteria

C

M

C

M

Baseline LSBE vs. SSBE

GERD symptoms

Sex

Age

BMI

HH (cm)

104

C

15

15

15

15

15

LSBE

Frequent

F

57

29.0

4.5

183

C

14

14

14

a

a

LSBE

Frequent

M

39

24.6

6.0

163

C

11

9

11

7

10

LSBE

Infrequent

M

53

43.6

3.0

187

C

3

3

3

2

3

LSBE

Frequent

M

73

29.8

4.0

190

C

2

0

2

0

2

SSBE

Frequent

M

75

28.9

2.0

182

D

8

0

2

0

2

SSBE

Frequent

M

65

29.4

2.0

185

D

4

6

6

LSBE

Absent

M

30

51.0

13.0

164

C

ND

5

6

LSBE

Frequent

M

71

26.3

4.0

131

C

ND

4

5

LSBE

Frequent

F

70

28.4

6.0

109

D

3

2

2

SSBE

Frequent

F

58

32.3

6.0

103

D

1

2

2

SSBE

Frequent

F

51

29.0

5.0

110

D

5

0

2

SSBE

Absent

F

77

28.8

6.0

149

D

ND

0

2

SSBE

Infrequent

F

43

45.6

3.0

Rows 1–4 and 7–9 indicate morning (control group) and rows 5, 6 and 10–13 indicate nighttime (experimental group) HH hiatal hernia length in cm at baseline endoscopy, C circumferential extent of Barrett’s esophagus mucosa per the Prague Classification System, GERD sx gastroesophageal Reflux Disease symptoms, LSBE long segment Barrett’s esophagus, M maximal extent of Barrett’s esophagus mucosa per the Prague Classification System, ND not described, SSBE short segment Barrett’s esophagus a

Lost to follow-up

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

123

assume subjects without follow-up questionnaire information have severe symptoms at follow-up. Thus, the statistically significant findings shown in Table 6 are

Dig Dis Sci

(a)

Heartburn Intention-To-Treat (worst case)

Morning vs Nighttime: Before and After Treatment with Omeprazole/Sodium Bicarbonate

Morning Dose

Nighttime Dose

Frequent

Infrequent

Absent

Before

After

After

Subjects had complete questionnaires

Key

(b)

Before

Subjects missing follow-up questionnaires

Acid Regurgitation Intention-To-Treat (worst case)

Morning vs Nighttime: Before and After Treatment with Omeprazole/Sodium Bicarbonate

Morning Dose

Nighttime Dose

Frequent

Infrequent

Absent

Before

After

Before

After

Subjects had complete questionnaires

Key

Subjects missing follow-up questionnaires

Fig. 4 a Frequency of heartburn before and after 8 weeks of omeprazole/sodium bicarbonate therapy comparing morning versus nighttime dosing. Intention-to-treat (worst case). b Frequency of acid regurgitation before and after 8 weeks of omeprazole/sodium bicarbonate therapy comparing morning versus nighttime dosing. Intention-to-treat (worst case)

7.

artifactual. Thus, we opted to show the Per-protocol results in the manuscript (see Table 2). Table 7 is the ITT (best case) version of Table 2. It shows the results for ITT best case scenario in which we assume subjects without follow-up

8.

questionnaire information are symptom free at 8 weeks. Detailed demographic information of 13 subjects ultimately diagnosed with Barrett’s esophagus (Table 8).

123

Dig Dis Sci

(a)

Heartburn Intention-To-Treat (best case)

Morning vs Nighttime: Before and After Treatment with Omeprazole/Sodium Bicarbonate

Morning Dose

Nighttime Dose

Frequent

Infrequent

Absent

Before

After

Before Subjects had complete questionnaires

Key

(b)

After

Subjects missing follow-up questionnaires

Acid Regurgitation Intention-To-Treat (best case)

Morning vs Nighttime: Before and After Treatment with Omeprazole/Sodium Bicarbonate

Morning Dose

Nighttime Dose

Frequent

Infrequent

Absent

Before

After

Key

Before

After

Subjects had complete questionnaires Subjects missing follow-up questionnaires

Fig. 5 a Frequency of heartburn before and after 8 weeks of omeprazole/sodium bicarbonate therapy comparing morning versus nighttime dosing. Intention-to-treat (best case). b Frequency of acid regurgitation before and after 8 weeks of omeprazole/sodium bicarbonate therapy comparing morning versus nighttime dosing. Intention-to-treat (best case)

References 1. 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. 2. 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.

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