The Impacts of On-demand Versus Continuous Esomeprazole Therapy on the Symptom Control and Histological Changes of Metaplastic Esophageal Epithelium in Patients With Barrett's Esophagus (EsoBE) - a Multicentre Randomized Controlled Trial
Phase: NA
Conditions: Barrett Esophagus, Proton Pump Inhibitor, Symptom, Reflux
Sponsor: Kaohsiung Veterans General Hospital.

 
Version: 08/26/2017 last approved 
Study Design 
Patients 
The open-labeled trial is conducted at the Kaohsiung Veterans General Hospital, 
Kaohsiung Medical University Hopsital and Kaohsiung Chang Gung Memorial 
Hospital in Taiwan in accordance with the principles of good clinical practice from the 
Declaration of Helsinki. The study protocol was approved by the Ethics Committees in 
each study center. All patients will be given written informed consent before 
participating in the study. Patients between the ages of 20 and 80 years with clinical 
symptoms of acid regurgitation, heart burn, or feeling of acidity in the stomach, who 
have Barrett's Esophagus proven by histology confirmation of esophageal metaplastic 
mucosa with length equal to or longer than 1 centimeter will be enrolled. Criteria for 
exclusions include (1) pregnancy, (2) coexistence of serious concomitant illness (for 
example, decompensated liver cirrhosis and uremia), (3) previous gastric surgery, (4) 
allergy to esomeprazole, (5) presence of dysplastic esophageal mucosa, and (6) 
equivocal endoscopic diagnosis of Barrett’s esophagus (e.g., esophageal metaplastic 
mucosa less than 1 cm).  
 
Study Design and Randomization 
Eligible patients will be randomly assigned to receive either (1) on-demand PPI 

 
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therapy (40 mg of esomeprazole [Nexium, AstraZeneca, Sodertalje, Sweden] daily 
for 8 weeks, and then on-demand esomeprazole 40 mg daily if symptoms recurred.)  
or (2) continuous PPI therapy (40 mg of esomeprazole daily for 48 weeks). 
Randomization will be carried out with the use of a computer-generated list of random 
numbers. An independent staff member assigns the treatments according to 
consecutive numbers that are kept in sealed envelopes. The participants in the on-
demand group will be instructed to take esomeprazole 40 mg daily for consecutive 
three days whenever reflux symptoms bothered them. If patients have obvious reflux 
symptoms soon after discontinuing PPI therapy twice or more, on-demand PPI 
treatment could be switched to continuous PPI use. In the continuous PPI therapy 
group, the participants take esomeprazole 40 mg daily no matter symptoms develop 
or not. All the participants are instructed to take esomeprazole 30 minutes before 
breakfast.  
They are requested to complete a Chinese GERDQ on enrollment. The total 
score of GERD symptoms will be recorded. Each participant should complete diary 
cards during the study period. They return to the clinics for drug refills and evaluation 
of reflux symptoms every month. The participants are asked to hand in daily symptom 
records at each visit, and to report the number of esomeprazole tablets taken per 4-
week period. Follow-up endoscopy with biopsy for esophageal mucosal metaplasia 

 
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will be performed at the end of 48 weeks.  
 
Endoscopy 
Endoscopy is performed on enrollment, and the esophagus is carefully evaluated. 
Endoscopic suspected esophageal metaplasia (ESEM) is defined as a tongue-shaped 
projection of salmon-colored mucosa from the esophagogastric junction (the point 
where the proximal end of the gastric folds meets the tubular esophagus). All of the four 
quadrants of ESEM will be sampled every 2 cm. The Barrett’s esophagus is defined as 
gastric or intestinal metaplastic change of distal esophageal epithelium confirmed by 
biopsy. The grade of Barrett’s esophagus is scored according to the Prague C & M 
criteria. All subjects with biopsy-proven Barrett’s esophagus will be further categorized 
into long-segment Barrett’s esophagus and short-segment Barrett’s esophagus. Long-
segment Barrett’s esophagus is defined as the maximal length of metaplastic columnar 
epithelium over distal esophagus equal to or more than 3 cm, and short-segment 
Barrett’s esophagus is defined as the extension of columnar epithelium over distal 
esophagus less than 3 cm. Erosive esophagitis will be scored using the Los Angeles 
classification system. Hiatus hernia is defined as a distance between the 
esophagogastric junction and the diaphragmatic hiatus equal to or more than 1 cm. 
 

 
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H pylori examination 
    Two biopsy specimens are taken from the lesser curvature sites of the antrum, 
and another two from the corpus. They will be fixed in 10% buffered formalin, 
embedded in paraffin, and sectioned. The sections, 4-μm thick, will be stained with 
a haematoxylin and eosin stain and a modified Giemsa stain to observe the presence 
of curved rod shape bacteria on the mucosal surface. Biopsy specimens will be 
assessed by histopathologists, who are blinded to patient status and the results of 
other laboratory tests. 
 
Questionnaire 
A standardized data-collection form for medical history and demographic data will 
be obtained from each patient on enrollment, including age, sex, body mass index 
(BMI), medical histories, histories of smoking, alcohol, coffee and tea consumption. 
Smoking is deﬁned as consumption of cigarettes 1 pack or more per week. Coffee or 
tea consumption is deﬁned as drinking 1 cup or more per day.  
Chinese GERDQ is a validated symptom questionnaire for the diagnosis and 
severity evaluation of gsatroesophageal reflux disease. In the scoring system, the 
evaluated symptoms include acid regurgitation, heartburn and feeling of acidity in the 
stomach. The severity of symptoms in the questionnaire are graded on a five-point 

 
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Likert scale as follows: 1 (none; no symptoms); 2 (mild: symptoms can be easily 
ignored); 3 (moderate: awareness of symptoms but easily tolerated); 4 (severe: 
symptoms sufficient to cause an interference with normal activities); 5 (incapacitating: 
incapacitating symptoms with an inability to perform daily activities or work), and 
frequency of symptoms are graded as follows: 1 (none in the past year); 2 (less than 
once per month); 3 ( once per month); 4 ( once per week); 5 ( once daily). A cut-off 
score of ≥12 is used to make the diagnosis of symptomatic GERD. 
 
Genotyping of CYP2C19 
Blood sampling for genotyping of CYP2C19 will be carried out after endoscopy 
for the subjects who provides informed consent for genetic study. The CYP2C19 
genotype is determined using the polymerase chain reaction-restriction fragment length 
polymorphism (PCR-RFLP). Genotypes are classified into three groups: homEM 
(CYP2C19*1/CYP2C19*1); 
hetEM 
(CYP2C19*1/CYP2C19*2 
and 
CYP2C19*1/CYP2C19*3); PM (CYP2C19*2/CYP2C19*2, CYP2C19*2/CYP2C19*3, 
and CYP2C19*3/CYP2C19*3). 
 
End Points 
The primary outcome measures are (1) histological progression of metaplastic 

 
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esophageal epithelium at 48 weeks, and (2) total symptom days within the 48-week 
study period. The secondary outcome measure is total PPI consumption during the 48-
week study period. Histological progression of metaplastic esophageal epithelium is 
defined as (1) progression from gastric metaplasia into intestinal metaplasia, low grade-
dysplasia or high-grade dysplasia, or (2) progression from intestinal metaplasia into 
low-grade or high-grade dysplasia.  
 
Statistics 
Our study is designed as a non-inferiority trial. Sample size was calculated from 
numbers needed to show that on-demand therapy is non-inferior to continuous therapy 
based on the proportion of patients who would discontinue the study prematurely 
because of unsatisfactory therapy. The hypothesis for sample size calculations are based 
on 94% on-demand therapy continuation rate and 92% continuous therapy continuation 
rate. On-demand therapy is defined as non-inferior to continuous therapy if the upper 
bound of the two-sided 90 % CI for the difference in proportions (on-demand minus 
continuous) is less than 10 %.  
With a sample size of 78 patients in each treatment group, a one-sided test of 
proportions at the 5 % level had 90 % power to reject the hypothesis that on-demand 
therapy is inferior to continuous treatment. With an assumption of 10 % non-evaluable 

 
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patients and 10% non-eligible patients for randomization, it was calculated that 196 
patients would be required in the initial enrollment to yield sufficient power. 
Statistical analysis will be performed using the Statistical Program for Social 
Sciences (SPSS 19.0 for windows). Univariate analysis is performed by Student’s t test 
for continuous variables andχ2 test is used for categorical variables. P < 0.05 is 
considered statistically significant and all reported p values are two-sided.