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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Background  Gastric acid control is important for treatment of gastro-oesophageal reflux disease associated with Barrett’s oesophagus. Substantial indirect evidence suggests that gastric acid control may have a chemopreventive role in Barrett’s oesophagus.

Aim  To compare the pharmacodynamic efficacy of esomeprazole and lansoprazole at two dosages for intragastric pH control with Barrett’s oesophagus.

Methods  Patients with Barrett’s oesophagus received open-label consecutive treatment (a 15-day period of once-daily dosing followed by a 10-day period of twice-daily dosing) with esomeprazole (40-mg capsules) and lansoprazole (30-mg capsules) in random order with no washouts. Twenty-four-hour intragastric pH was recorded on the last day of each dosing period. The primary end point was the percentage of time with intragastric pH > 4.0.

Results  In the per-protocol once- (= 46) and twice-daily (= 41) analyses, the percentage of time with intragastric pH > 4.0 was significantly (< 0.0001) longer after once- (67.1%) or twice-daily (81.2%) esomeprazole than after once- (50.8%) or twice-daily (64.3%) lansoprazole. The proportion of patients with intragastric pH > 4.0 for >12 h was significantly higher for esomeprazole than lansoprazole with once- (= 0.004) and twice-daily (= 0.016) dosing.

Conclusion  Esomeprazole 40 mg is significantly more effective than lansoprazole 30 mg in controlling intragastric pH with Barrett’s oesophagus.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Barrett’s oesophagus (BO), a consequence of chronic gastro-oesophageal reflux disease (GERD), is an important risk factor for oesophageal adenocarcinoma, a tumour the frequency of which has increased dramatically in the past several decades.1, 2 BO develops when refluxed gastric material damages the squamous lining of the oesophagus and the injury heals through a metaplastic process in which the reflux-damaged squamous epithelium is replaced by an intestinal-type columnar epithelium.1, 2 The intestinal metaplasia that characterizes BO is predisposed to malignancy.

Adenocarcinomas in BO evolve through a series of genetic alterations in the metaplastic cells. A number of studies have suggested that the development of those genetic alterations may be facilitated by continued exposure to refluxed gastric acid. For example, acid has been shown to cause DNA double-strand breaks in adenocarcinoma cells and to activate proliferation pathways in Barrett’s epithelium in vivo and in biopsy specimens of Barrett’s epithelium that are maintained in organ culture.3–6

Clinical studies of patients who have BO have suggested that effective acid suppression may decrease proliferation in their metaplastic epithelium. In one study in which biopsy specimens of Barrett’s epithelium were taken from patients at baseline and after 6 months of antisecretory therapy, the expression of proliferating cell nuclear antigen (a proliferation marker) significantly decreased in biopsy specimens from 24 patients in whom treatment had normalized oesophageal acid exposure, but not in 15 patients who had persistently abnormal acid reflux.7 Another report described no significant change in the proliferative activity of Barrett’s epithelium in 22 patients treated with a proton pump inhibitor (PPI) for 2 years, whereas proliferative activity increased significantly in 23 patients treated for the same length of time with histamine2-receptor antagonists.8 Furthermore, a long-term retrospective study of 236 patients with BO who received a number of different antireflux therapies showed that at 10 years, the cumulative incidence of dysplasia was 21% in patients who received PPIs compared with 58% in patients who did not receive PPIs.9 Another study investigating whether treatment with PPIs influenced the incidence and progression of oesophageal dysplasia in 350 patients with BO showed that the risk of developing low-grade dysplasia was 5.6 [95% confidence interval (CI) 2.0–15.7] times higher in patients who started PPI therapy 2 years or more after the time of diagnosis than in patients who started PPI therapy in the first year. In addition, the delay of PPI therapy increased the risk of developing high-grade dysplasia or adenocarcinoma by a factor of 20.9 (95% CI 2.8–158).10 These studies all provide indirect evidence that effective acid suppression may help prevent oesophageal cancer in patients who have BO.

The PPI esomeprazole has been shown to control intragastric and intraoesophageal acidity in patients who have BO.11, 12 A study comparing esomeprazole and lansoprazole treatments for GERD patients who do not have BO showed that esomeprazole 40 mg controlled intragastric pH more effectively than lansoprazole 30 mg at equivalent dosing regimens.13 The purpose of this study was to compare the pharmacodynamic efficacy of esomeprazole and lansoprazole at two different dosages for the control of intragastric pH in patients who have BO.

Methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Patients

Patients eligible for the study were aged 18–70 years and had a history (within the past 2 years) of histologically proven BO (intestinal-type columnar epithelium ≥ 2 cm), tested (by serology) negative for Helicobacter pylori and had no high-grade dysplasia or adenocarcinoma. Patients were excluded from the study if they had clinically significant illness ≤2 weeks before the first dose of study medication or during the study, gastrointestinal (GI) bleeding ≤3 days before randomization or a history of gastric or oesophageal surgery (including Nissen fundoplication or endoscopic fundoplication), but not simple closure of perforated ulcer. Additional exclusion criteria were generalized bleeding disorders resulting from haemorrhagic diatheses; current or recent (≤3 months before baseline endoscopy) evidence of significant GI disease; severe cardiovascular, pulmonary, liver or renal disease; active malignant or infectious disease (e.g. tuberculosis, acute hepatitis, acquired immunodeficiency syndrome); unstable diabetes mellitus; seizure disorder; cerebral vascular disease and any condition potentially requiring surgery during the study.

Patients also were excluded if they had an endoscopy for surveillance of BO 14 days before or during the study. Concomitant medications not permitted included acetylsalicylic acid >162 mg/day, anticoagulants, antiretroviral agents, antineoplastic agents, prostaglandin analogs, oral or intravenous corticosteroids, promotility drugs, anticholinergic drugs, daily narcotics, sucralfate, histamine2-receptor antagonists, antacids [other than rescue antacid (Gelusil [aluminum hydroxide, magnesium hydroxide and simethicone; Parke Davis, Morris Plains, NJ, USA]) provided through the study], nonsteroidal anti-inflammatory drugs >3 days/week, PPIs not provided through the study and any medication requiring the presence of gastric acid for optimal absorption. Patients with intolerance or lack of response to PPIs and pregnant or lactating women also were excluded from the study. Women of child-bearing potential had to use a medically acceptable form of birth control throughout the study.

Study design

The primary objective of this multicentre, randomized, open-label, crossover study was to compare the efficacy of oral once-daily doses of esomeprazole (Nexium; AstraZeneca, Wilmington, DE, USA) and lansoprazole (Prevacid; TAP Pharmaceuticals Inc., Lake Forest, IL, USA) for intragastric pH control in patients who have BO (D9612L00082; ClinicalTrials.gov Identifier NCT00352261). Patients were randomized to 1 of 2 treatment sequences in sequential blocks of 2 (Figure 1). Patients assigned to sequence 1 were treated with esomeprazole 40 mg once daily for 15 days followed by esomeprazole 40 mg twice daily for 10 days and then crossed over to treatment with lansoprazole 30 mg once daily for 15 days followed by lansoprazole 30 mg twice daily for 10 days. Patients assigned to sequence 2 were treated first with lansoprazole 30 mg and then with esomeprazole 40 mg in a manner similar to that used in sequence 1. Study medication was prescribed to be taken 30 min before breakfast for once-daily dosing or 30 min before breakfast and dinner for twice-daily dosing. A washout period was not included between drug treatments to prevent treatment interruptions for patients with GERD symptoms requiring continual treatment. Gelusil was provided as rescue therapy for acute GERD symptoms.

image

Figure 1.  Study design. E40 = esomeprazole 40 mg; L30 = lansoprazole 30 mg.

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The primary end point was the percentage of time with intragastric pH > 4.0 (% time pH > 4.0) during the monitoring period after the once-daily dosing intervals. For each patient, the percentage of time pH > 4.0 was defined as the number of pH values with pH > 4.0 divided by the total number of values obtained during monitoring multiplied by 100. pH values of 0 or ≥9 were excluded. Secondary end points included the percentage of time pH > 4.0 after twice-daily dosing intervals, the change in percentage of time pH > 4.0 related to dosing increase from once to twice daily and the number of patients with intragastric pH > 4.0 for >12 h. The change in percentage of time pH > 4.0 resulting from increased dosing with esomeprazole or lansoprazole was calculated for each treatment group within a patient as percentage of time pH > 4.0 related to twice-daily dosing minus the percentage of time pH > 4.0 related to once-daily dosing. Patients were considered to have had pH > 4.0 for >12 h if the percentage of time pH > 4.0 was ≥50% based on valid pH values recorded.

The study protocol was approved by the Institutional Review Board for each study centre. All patients provided written informed consent before any study-specific procedure was executed. Study procedures were conducted in accordance with the ethical principles of the Declaration of Helsinki and consistent with ICH/Good Clinical Practice.

Intragastric pH assessments

Intragastric pH was evaluated using a catheter-based method on or after days 14 and 9 of the once- and twice-daily dosing intervals respectively (Figure 1). A microelectrode attached to a GERDcheck® data logger (Sandhill Scientific, Inc., Highlands Ranch, CO, USA) was used for pH recording. The calibrated pH microelectrode was positioned 10 cm below the lower oesophageal sphincter (LES) and the proximal electrode was placed 5 cm above the LES using the LES locator or by formal manometric localization. The position of the electrode placement was recorded during the first pH monitoring test to allow consistent placement during subsequent pH recordings. After placement of the pH probes, patients received study medication and pH values were recorded every 5 s for 24 h. The validity of the pH data was assessed programmatically by two independent, blinded central reviews (Dr Yu-Xiao Yang and Dr Philip Katz). Valid pH data had ≥20 h of pH values within the reference range (pH 0–9, exclusive), with the distal (intragastric) pH data not outside the reference range for ≥1 continuous hour and acceptable technical aspects of the pH recording.

A low-fat, low-calorie breakfast was provided 30 min after the study medication was administered. For twice-daily dosing, an evening dose was administered 30 min before dinner. Patients were instructed to refrain from lying down until 10 pm, beginning any new physical training activities and ingesting anything but necessary nonstudy medications after midnight before each pH monitoring period. Gelusil intake before or during pH monitoring also was not permitted.

Safety assessments

Adverse events (AEs) were reported spontaneously by the patient or in response to open questioning by the study investigator. Changes from baseline values in clinical laboratory tests, vital signs and physical examination also were evaluated.

Statistical analysis

The primary analysis population was the per-protocol (PP) population, which consisted of all patients who completed both comparative treatment sequences, had valid pH data for both comparative sequences and had no major protocol violations or deviations. To verify the conclusions from PP population-based analyses, confirmatory sensitivity analyses were conducted with extended intention-to-treat (ITT) populations, which included patients with evaluable pH data (data that met all criteria of pH validity that could be programmatically verified without the additional assessment by the central reviewer) for at least one treatment period (e.g. after the esomeprazole and/or the lansoprazole treatment period for a particular end point).

For analysis of the percentage of time pH > 4.0, mixed statistical models with fixed effects for treatment, treatment sequence and treatment period were used to determine least square means (LSMs), standard errors of the means (S.E.M.), 95% CIs, and P values for differences between treatment groups. The comparison of the percentages of patients with intragastric pH > 4.0 for >12 h was performed by McNemar’s matched pairs test. For comparison of the change in the percentage of time pH > 4.0, a mixed model with fixed effects for treatment and treatment sequence and a random effect for patients nested within a treatment sequence was used. All statistical tests were conducted at the 2-sided 5% significance level, and CIs were 2 sided.

A sample size of 80 patients was expected to provide ≥60 patients qualifying for inclusion in the PP population. This number was calculated to be sufficient to provide 90% power to detect a difference of 7.75 percentage points between treatment groups for the primary end point of percentage of time with pH > 4.0 in 24 h based on a within-patient standard deviation (s.d.) of 12.9% and an overall significance level of 0.05 in a 2-tailed test.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

The study was conducted at 14 centres in the United States between January 2006 and April 2007. Of the 113 patients randomized, pH studies were not valid for 37 of 86 patients who completed both pH assessments for once-daily dosing, two additional patients had poor compliance and one patient refused breakfast the morning of one of the pH assessments for once-daily dosing (n = 46). Similarly, of the 113 patients randomized, pH studies were not valid for 39 of 80 patients who completed both pH assessments for twice-daily dosing (n = 41). A total of 37 patients had valid pH data for both once- and twice-daily dosing. The primary and secondary PP populations were smaller than originally planned because a larger proportion of pH data than expected failed to meet all the criteria for validity (likely attributable to improper pH probe placement). Of the patients who completed pH assessments and did not have a major protocol violation or deviation (83 and 79 patients for once- and twice-daily dosing, respectively), 37 and 38 patients respectively were removed from the PP population after blinded review of the pH data (primarily because of suspected misplacement of the pH probe). Most patients were white men with high body mass indices (BMI; mean 30.5 kg/m2) (Table 1).

Table 1.   Patient demographic and baseline clinical characteristics (PP population)
CharacteristicOnce-daily dosing (= 46)Twice-daily dosing (= 41)All randomized patients (= 113)
Men, n (%)31 (67.4)27 (65.9)82 (72.6)
Women, n (%)15 (32.6)14 (34.1)31 (27.4)
Age in years, mean (s.d.)58.1 (7.2)58.9 (6.6)56.0 (9.1)
 Range41–7043–6931–70
Race, n (%)
 White44 (95.7)40 (97.6)109 (96.5)
 Other2 (4.3)1 (2.4)4 (3.5)
BMI, kg/m2, mean (s.d.)30.2 (5.5)30.6 (6.1)30.5 (5.7)
 Range20.5–47.420.5–47.419.7–47.4

Efficacy

During the 24-h monitoring period after once- or twice-daily dosing intervals, intragastric pH values were >4.0 for a longer percentage of time with esomeprazole 40 mg than with lansoprazole 30 mg (< 0.0001; Figures 2 and 3). Once-daily administration of esomeprazole 40 mg resulted in pH > 4.0 for 67.06% of the 24-h period, or 16.1 h, compared with 50.81% of the 24-h period, or 12.2 h, for the corresponding dose of lansoprazole (< 0.0001). Twice-daily dosing of esomeprazole 40 mg resulted in pH > 4.0 for 81.2% of the 24-h period, or 19.5 h, compared with 64.31% of the 24-h period, or 15.4 h, for twice-daily dosing of lansoprazole 30 mg (< 0.0001).

image

Figure 2.  Least square mean percentage of time during the 24-h monitoring period with intragastric pH > 4.0. *< 0.0001 (esomeprazole vs. lansoprazole for once and twice daily). Error bars indicate 95% confidence intervals.

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image

Figure 3.  Percentage of time during the 24-h monitoring period with intragastric pH > 4.0 by patient and treatment regimen. E40 = esomeprazole 40 mg; L30 = lansoprazole 30 mg.

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The change in the percentage of time pH > 4.0 related to dosing increase from once to twice daily was greater for esomeprazole (LSM 18.3; S.E.M. 2.5) than for lansoprazole (LSM 16.5; S.E.M. 2.5). The difference, however, was not statistically significant (LSM 1.9%; S.E.M. 3.4%; = 0.59), although, as noted previously, esomeprazole yielded significantly better acid suppression than lansoprazole under once- and twice-daily dosing regimens. For both dosing regimens, the proportion of patients with intragastric pH > 4.0 for >12 h was significantly higher among those receiving esomeprazole 40 mg than those receiving lansoprazole 30 mg (once daily = 0.0004; twice daily = 0.0156; Figure 4).

image

Figure 4.  Percentage of patients who had intragastric pH > 4.0 for >12 h. *= 0.0004 (esomeprazole once daily vs. lansoprazole once daily). **= 0.0156 (esomeprazole twice daily vs. lansoprazole twice daily).

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To assess the robustness of the results obtained with the PP populations, sensitivity ITT analyses of the percentage of time with pH > 4.0 using all available pH data deemed valid by programmatic checks were performed, thus removing all subjectivity from the assessment of pH validity. Of the 96 patients included in the once-daily analysis, 92 received esomeprazole and 89 received lansoprazole; of the 88 patients included in the twice-daily analysis, 84 received esomeprazole and 82 received lansoprazole. In the once-daily and twice-daily analyses, the percentage of time with pH > 4.0 was significantly (< 0.0001) longer with esomeprazole (LSM 78.2% and 89.4%, respectively) than lansoprazole (LSM 67.9% and 77.7% respectively), although the model estimated higher LSMs because of the inclusion of patients with suspected probe misplacement and oesophageal tracings.

Safety

Adverse events were reported by 38 patients (33.9%) in the safety population (= 112). The most common AEs among patients while receiving esomeprazole were pharyngolaryngeal pain, sinusitis and headache. In contrast, the most common AEs in patients while receiving lansoprazole were diarrhoea, nausea, anxiety and headache (Table 2).

Table 2.   Patients n (%) experiencing AEs occurring in ≥2% of the total safety population
AEEsomeprazole 40 mgLansoprazole 30 mg
Once daily (= 102)Twice daily (= 92)Once daily (= 98)Twice daily (= 91)
Diarrhoea01 (1.1)5 (5.1)2 (2.2)
Anxiety1 (1.0)1 (1.1)4 (4.1)0
Headache1 (1.0)2 (2.2)2 (2.0)1 (1.1)
Nausea005 (5.1)1 (1.1)
Pharyngolaryngeal pain1 (1.0)3 (3.3)01 (1.1)
Sinusitis3 (2.9)000
Fatigue002 (2.0)0
Flatulence2 (2.0)000
Hypertension02 (2.2)00
Pain in extremity1 (1.0)02 (2.0)0

A total of four patients discontinued from the study because of AEs. Although all patients were being treated with lansoprazole at the time of discontinuation, none of the events were considered related to treatment. Two AEs (cholelithiasis and cholecystitis) resulting in discontinuation were serious and occurred in a single patient during lansoprazole twice-daily treatment. Another patient receiving lansoprazole twice daily suffered from diarrhoea unrelated to treatment during the study. This event was not considered serious when reported but became serious after the patient discontinued study participation. Only two patients experienced treatment-related AEs, both after receiving once-daily doses of lansoprazole. These events included a total of three occurrences of diarrhoea and one occurrence of abdominal pain. Although increased serum creatinine levels were reported for six patients – five during lansoprazole treatment – none of the increases was considered clinically significant.

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Proton pump inhibitor therapy has been shown to heal reflux oesophagitis and to control GERD symptoms in patients who have BO.14 In its recent guidelines for the diagnosis, surveillance and therapy of BO, the Practice Parameters Committee of the American College of Gastroenterology advises that twice-daily dosing of PPIs may be necessary to achieve effective symptom relief in some patients who have BO,15 even though such dosing is not approved by the Food and Drug Administration. Although no direct evidence shows that effective control of acid reflux prevents cancer in BO, substantial indirect evidence supports that concept and some authorities have recommended PPIs as first-line therapy for patients who have BO.1 In the near future, direct evidence of efficacy in preventing oesophageal cancer is likely to remain elusive for any medication currently used to treat patients who have BO. However, recruiting is currently under way for a large, randomized, phase 3 trial aimed at evaluating the efficacy of esomeprazole, with or without aspirin, in preventing oesophageal cancer in patients who have Barrett’s metaplasia.16

The results of the present study show that once- or twice-daily oral administration of esomeprazole provides significantly better control of intragastric acidity than similar dosing regimens of lansoprazole in patients who have BO. Twice-daily dosing of both drugs provided a better intragastric pH control than once-daily dosing, and the relative gains in intragastric acid control resulting from dose escalation were similar with both drugs. The doses of esomeprazole (40 mg) and lansoprazole (30 mg) used in this study were chosen because they are the highest single doses approved by the Food and Drug Administration for a GERD indication. Esomeprazole and lansoprazole were well tolerated at both doses.

Although 113 patients were enrolled in this study, only 46 were eligible for some of the PP analyses. This result stemmed primarily from an unexpectedly high number of pH measurements that were technically unacceptable, probably because of improper probe placement. Despite the smaller-than-planned PP population, the study was still able to demonstrate highly statistically significant differences in intragastric acidity between the two treatment groups after once- and twice-daily dosing. The robustness of the PP population-based analyses for all end points was substantiated by statistical sensitivity analyses of corresponding extended ITT populations, which included patients with programmatically verified evaluable pH data who may have been excluded from the PP population as a result of the potentially subjective assessment of the pH tracing by the central reviewer. The results obtained with the extended ITT populations were consistent and supportive of the conclusions drawn from the PP analyses.

To avoid clinically unacceptable interruptions in PPI treatment, no washout periods were mandated between treatment intervals. However, the length of the dosing periods before each 24-h pH monitoring period (i.e. 15 days for once-daily dosing and 10 days for twice-daily dosing) ensured that, at the time of pH monitoring, steady state levels of the study drug had been achieved and the possibility of carryover effects from the previous treatment had been minimized.

The results of this study are consistent with those of a previous study that compared the pharmacodynamic efficacy of different dosages of esomeprazole in patients who have BO.11 Esomeprazole 40 mg 3 times daily was significantly more effective for control of intragastric pH than esomeprazole 40 mg twice daily or esomeprazole 20 mg 3 times daily.11 For esomeprazole 40 mg twice daily, the percentage of time pH was >4.0 (81.4%) was similar to that found for esomeprazole 40 mg twice daily in the present study (81.2%).

This study’s findings showed that, in patients who have BO, esomeprazole 40 mg once daily achieved statistically significant better control of intragastric pH than lansoprazole 30 mg once daily. There also was a statistically significant advantage for intragastric acid suppression with esomeprazole 40 mg vs. lansoprazole 30 mg with twice-daily dosing. Both therapies were more effective at the higher dose and well tolerated at either dose. Overall, the results suggest that at comparable doses, esomeprazole suppresses gastric acidity more effectively than lansoprazole in patients who have BO.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Declaration of personal interests: Stuart J. Spechler has received research funding from AstraZeneca LP and Takeda Pharmaceuticals. Drs Barker and Silberg are employees of and own stocks and shares in AstraZeneca LP. The authors would like to thank Dr Yu-Xiao Yang (University of Pennsylvania, Philadelphia, PA) and Dr Philip Katz (Albert Einstein Medical Center, Philadelphia, PA) for validating the pH data. The authors also would like to thank the investigators who recruited patients for the study: Ajay Bansal, MD (Kansas City, MO), Florian Cortese, MD (Brute, MT), Gary Falk, MD (Cleveland, OH), Axel Feller, MD (North Chicago, IL), Kelvin Hornbuckle, MD (Norfolk, VA), Vikram S Jayanty, MD (Houston, TX), David Katzka, MD (Philadelphia, PA), Paul Milner, MD (Jackson, MS), Sam Moussa, MD, (Tucson, AZ), Francisco Ramirez, MD (Phoenix, AZ), Dennis Riff, MD (Anaheim, CA), Ken Wang, MD (Rochester, MN), Allan Paul Weston, MD (Springfield, MO). Declaration of funding interests: This study was funded in full by AstraZeneca LP. The writing of this paper was funded by AstraZeneca LP. Initial data analyses were undertaken by Peter N. Barker and Debra G. Silberg, who are employees of AstraZeneca. Writing support was provided by Lisa M. Klumpp, PhD, and Judy Fallon, PharmD, of Scientific Connexions, Newtown, PA, and funded by AstraZeneca LP.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
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    US National Institutes of Health Clinical Trials Registry. NCT00357682. Esomeprazole with or without aspirin in preventing oesophageal cancer in patients with Barrett’s metaplasia. http://www.clinicaltrials.gov/ct2/results?term=NCT00357682. Accessed January 12, 2009.