Trial Oversight

We conducted a single-center, double-blind, randomized, placebo-controlled trial at the National Cancer Center in South Korea. All the patients provided written informed consent before enrollment. The trial was approved by the institutional review board at the National Cancer Center and was conducted in accordance with the provisions of the Declaration of Helsinki.24 An independent data and safety monitoring board reviewed the progress of the trial.

The trial was designed by the lead author and supported by grants provided by the National Cancer Center. The trial investigators collected and analyzed the data. All the authors vouch for the accuracy and completeness of the data and analyses and for the adherence of the trial to the protocol (available with the full text of this article at NEJM.org). The first draft of the manuscript was written by the first author with assistance from the coauthors; all the authors made the decision to submit the manuscript for publication. The trial was not registered until all the patients had been enrolled because registration was not mandated until after the trial had started.

Patients

Patients between the ages of 18 and 75 years were eligible if they had histologically differentiated early gastric cancer or high-grade adenoma, as confirmed on endoscopic biopsy, and were scheduled for endoscopic resection. Major inclusion criteria included current H. pylori infection, endoscopic localization of a mucosal tumor without ulceration, and no lymph-node or distant-organ metastasis on computed tomography. Exclusion criteria included recurrent gastric cancer, previous H. pylori eradication treatment, histologic types of poorly differentiated tubular adenocarcinoma or signet-ring-cell carcinoma, a history of serious side effects associated with antibiotic therapy, the need for additional surgical resection after endoscopic resection,11 and cancer of another organ within 5 years before enrollment.

Trial Design and Treatment

Before endoscopic resection, patients were randomly assigned in a 1:1 ratio to receive either H. pylori eradication therapy or placebo. The stratification factor was the severity of the baseline grade of histologic atrophy at the antrum. Computer-generated randomization was performed in a blinded manner, with status concealed from all the patients and the primary physician, endoscopist, pathologist, and statistician. After randomization, endoscopic resection was performed as described previously.25 The patients started the assigned trial medication within 1 week after endoscopic resection.

In the treatment group, amoxicillin (1000 mg), clarithromycin (500 mg), and the proton-pump inhibitor rabeprazole (10 mg) were given twice daily for 7 days. In the placebo group, rabeprazole (10 mg) and placebo pills were administered. The proton-pump inhibitor was maintained in both groups for an additional 4 weeks to promote ulcer healing.

Participants underwent endoscopic evaluation at 3 months, 6 months, 1 year, and then every 6 months or 12 months until the last enrolled patient reached the 3-year follow-up. Data were censored at the last endoscopic examination for patients who were lost to follow-up or withdrew from the trial. For ethical reasons, quadruple therapy with a proton-pump inhibitor, bismuth, metronidazole, and tetracycline was provided for 10 days if H. pylori infection was detected at the closeout endoscopic examination, starting in September 2015.

Assessments

Endoscopic biopsy specimens for histologic evaluation of glandular atrophy and intestinal metaplasia were obtained from the gastric antrum lesser, corpus lesser, and corpus greater curvature at baseline, at 3 months, and at 36 months after randomization. According to criteria of the updated Sydney System for the classification of gastritis,26 glandular atrophy and intestinal metaplasia were scored as absent, mild, moderate, or marked (0, 1, 2, or 3, respectively).

H. pylori infection status was determined by a rapid urease test on samples obtained from the corpus greater curvature and by Wright–Giemsa staining of biopsy specimens from the three predefined sites. Any positive result defined H. pylori infection, except in the initial eligibility evaluation, which required at least two positive results.

The WHO classification system was used for histologic classification of gastric cancer.27 Diagnostic criteria for adenoma and cancer were adopted from the Vienna classification,28 which divides gastrointestinal epithelial lesions into five categories (with additional subcategories) as follows: category 1, no neoplasia or dysplasia; category 2, indefinite for neoplasia or dysplasia; category 3, noninvasive low-grade neoplasm; category 4, high-grade neoplasm; and category 5, invasive neoplasm (Table S1 in the Supplementary Appendix, available at NEJM.org). In our trial, category 4.3 (suspicion of invasive carcinoma) or higher was considered to be indicative of definite gastric cancer and categories 3 to 4.2 (carcinoma in situ) were considered to be adenomas.

Outcomes

The trial had two primary outcomes: the incidence of metachronous gastric cancer, which was defined as a gastric cancer detected on endoscopy at the 1-year follow-up or later, and the improvement from baseline of at least one grade of glandular atrophy at the corpus lesser curvature at the 3-year follow-up. Biopsy samples were evaluated by the study pathologist in a blinded manner.

Secondary outcomes included the incidence of metachronous adenoma and the overall survival rate. Overall survival was defined as the interval between the initiation of a trial medication and the date of death from any cause or June 30, 2016.

Statistical Analysis

We calculated the sample size using two primary outcome variables. For the first primary outcome of metachronous gastric cancer, we assumed that the annual incidence of this condition was 3%. We calculated that 180 patients in each trial group would provide a power of 80% to detect a hazard ratio of 0.50 in the treatment group, as compared with the placebo group, allowing for a 9-year accrual period and 3-year follow-up after the completion of enrollment. For the second primary outcome of histologic assessment, we calculated that 157 patients in each trial group would provide a power of 80% to determine a higher proportion of patients showing improvement of at least one grade of atrophy at the gastric corpus lesser curvature in the treatment group than in the placebo group (20% vs. 10%). We tested the two primary outcomes sequentially, as follows: the first primary outcome was tested at a two-sided significance level of 0.05; if the between-group difference was significant, then the second primary outcome was tested at a two-sided significance level of 0.05. From the calculations for both primary outcomes, we chose the larger sample size of 180 patients in each group for the trial population. We allowed for a 15% initial dropout rate, owing to the requirement of an additional surgery for noncurative endoscopic resection, and a further 10% loss to follow-up, resulting in the enrollment of 235 patients in each group. An interim analysis was not planned.

All the analyses were performed on a modified intention-to-treat principle. To evaluate the first primary outcome, we used the Kaplan–Meier method to estimate the incidence curve for metachronous cancer and Cox proportional-hazard models to estimate hazard ratios and 95% confidence intervals. To investigate the second primary outcome, we used a binary logistic-regression model to calculate the odds ratio for histologic improvement from baseline. In addition, we used a z-test statistic to compare the number of cases of metachronous cancer divided by the total person-time accumulated. All statistical analyses were performed with the use of SAS software (version 9.4) and R software (version 3.3.0).