Surgical Endoscopy (2019) 33:1376–1385 and Other Interventional Techniques https://doi.org/10.1007/s00464-018-6412-9 Effect of ilaprazole on the healing of endoscopic submucosal dissection-induced gastric ulcer: randomized-controlled, multicenter study Chang Seok Bang1,2 · Woon Geon Shin1,3 · Seung In Seo1 · Min Ho Choi1 · Hyun Joo Jang1 · Se Woo Park1 · Sea Hyub Kae1 · Young Joo Yang1 · Suk Pyo Shin1 · Gwang Ho Baik1 · Hak Yang Kim1 Received: 18 May 2018 / Accepted: 24 August 2018 / Published online: 30 August 2018 © Springer Science+Business Media, LLC, part of Springer Nature 2018 Abstract Background The optimal treatment regimen or the duration of treatment for an endoscopic submucosal dissection (ESD)- induced gastric ulcer has not been established. The aim of this study was to assess the efficacy of novel proton-pump inhibitor, ilaprazole, for the treatment of ESD-induced gastric ulcer. Methods This was a prospective, open-label, randomized multicenter study. Between June 2015 and March 2018, a total of 176 patients (178 lesions) who underwent ESD for a gastric neoplasm were randomly allocated to receive the oral proton- pump inhibitor ilaprazole 20 mg or rabeprazole 20 mg daily for 8 weeks. The primary outcome was the ulcer healing rate at 4 and 8 weeks. Results A total of 155 (157 lesions) and 154 patients (156 lesions) were included in the modified intention-to-treat (mITT) and per-protocol analyses, respectively. There was no significant difference in the ulcer healing rate (ilaprazole vs. rabepra- zole, 97.4% vs. 97.0 p = 0.78 at 4 weeks, 100% vs. 100%, p = 0.95 at 8 weeks in the mITT analysis) or stage of ulcer (scar stage, 25.6% vs. 17.7%, p = 0.25 at 4 weeks, 92.3% vs. 88.6%, p = 0.59 at 8 weeks in the mITT analysis) between the treat- ment groups. The quality of ulcer healing was not significantly different between the two groups. No independent predictive factor for higher-quality ulcer healing was found in the multivariate analysis. Conclusions According to this trial, ilaprazole and rabeprazole showed no significant difference in the healing of artifi- cial gastric ulcers. Most of the ulcers achieved complete healing within 4–8 weeks. Trial registration: ClinicalTrial.gov NCT02638584. Keywords Gastric ulcer · Endoscopic submucosal dissection · Ilaprazole · Rabeprazole · Endoscopy Abbreviations mITT Modified intention-to-treat ESD Endoscopic submucosal dissection PP Per-protocol PPI Proton-pump inhibitor IQR Interquartile range H. pylori Helicobacter pylori SD Standard deviation KGSRS Korean form of Gastrointestinal Symptom Rat- OR Odds ratio ing Scale CI Confidence interval n Number * Woon Geon Shin BMI Body mass index [email protected] 1 Department of Internal Medicine, Hallym University College Endoscopic submucosal dissection (ESD) has been estab- of Medicine, Chuncheon, South Korea lished as a primary treatment option for a specific subset of 2 Institue of New Frontier Research, Hallym University patients with gastric neoplasms who have a negligible risk of College of Medicine, Chuncheon, South Korea lymph node metastasis [1, 2]. With technical advancements, 3 Division of Gastroenterology, Department of Internal treatment outcomes in patients with gastric neoplasms who Medicine, Hallym University Kangdong Sacred Heart Hospital, 150 Seongan-ro, Gangdong-gu, Seoul 05355, meet the criteria for endoscopic resection have reached a South Korea level comparable to those of surgical resection [3, 4]. ESD Vol:.(1234567890)1 3 Surgical Endoscopy (2019) 33:1376–1385 1377 has the advantage of an en bloc resection of neoplastic tissue known hypersensitivity to any component of ilaprazole; and is less invasive than surgery because the stomach is pre- (2) taking a medication contraindicated with experimental served if curative resection is achieved. However, to achieve and concomitant drugs; (3) abnormal levels of laboratory clear resection margins, this procedure inevitably leaves a tests (serum total bilirubin or creatinine > 1.5 times the large and deep ulcer, which can lead to major complica- upper limit of normal and alanine transaminase, aspartate tions. Hemorrhage of the ESD-induced ulcer is immediately transaminase, alkaline phosphatase, and blood urea nitro- treated during the procedure; however, delayed bleeding is gen > 2 times upper limit of normal); (4) history of malig- also a drawback of ESD [1]. Proton-pump inhibitors (PPIs) nancy within 5 years other than gastric cancer; (5) history are the most widely used anti-ulcer medication and are cur- of Zollinger-Ellison syndrome, Barrett’s esophagus, primary rently the standard treatment, not only in patients with pep- esophageal motility abnormality, esophageal strictures, pan- tic ulcers but also in patients with ESD-induced artificial creatitis, malabsorption, severe cardiovascular or pulmonary gastric ulcers. We previously reported that a combination disease; (6) history of major surgery that can affect gastric therapy of oral PPI and rebamipide, a mucosa-protective acid secretion; (7) cannot discontinue the following medi- agent, for 4 weeks is more effective than oral PPI mono- cations during the study period: anticholinergics, motility- therapy in terms of the healing rate and quality of healing of promoting agents, prostaglandin analogs, sucralfate, aspi- ESD-induced gastric ulcers [5]. However, the optimal treat- rin, steroids, and nonsteroidal anti-inflammatory drugs; (8) ment regimen (intravenous vs. oral, continuous infusion vs. uncontrolled organ failure (liver dysfunction or renal dys- intermittent injections, once daily vs. twice daily, etc.) or function); and (9) pregnant and/or breast feeding women. duration of treatment for ESD-induced gastric ulcers has not been established. Study design Ilaprazole (Noltec®; IL-YANG Pharmaceutical Co., Ltd., Seoul, Korea) has a prolonged plasma half-life compared This was a prospective, open-label, randomized multicenter to other available PPIs and is not significantly influenced study. Sample size was calculated by using an α-error < 0.05 by CYP2C19 polymorphisms, which limits the efficacy of and a β-error < 0.2 with a two-tailed significance test. The a PPI [6, 7]. This medication is also known to provide bet- calculated number of lesions required for the study was ter pH control over 24 h without plasma gastrin concen- 70 in each arm, determined by assuming a healing rate of tration elevation compared with esomeprazole [8]. Rabe- 87% over 8 weeks of treatment with a 2nd-generation oral prazole, which is a 2nd-generation PPI like esomeprazole, PPI based on a previous study, a non-inferiority margin of was reported to have a stronger acid suppressing efficacy 15%, and a drop rate of 10% [13]. All patients were given than 1st-generation PPIs [8, 9]. It is also less affected by intravenous injections of pantoprazole 40 mg on the first CYP2C19 polymorphisms, which is more prevalent in East 2 days after ESD. Oral feeding was initiated on the second Asian countries than Western countries [10]. Although there day after performing the 2nd-look endoscopy to check for are theoretical advantages of these drugs, the comparative post-ESD hemorrhage. Patients with bleeding resumed their efficacy of ilaprazole with rabeprazole for the treatment of diet after confirming complete hemostasis. On the third day, ESD-induced artificial gastric ulcers has not been evaluated. the patients who met the inclusion and exclusion criteria Therefore, we assessed the comparative efficacy of ilapra- were randomly assigned to the ilaprazole or the rabeprazole zole and rabeprazole for the treatment of ESD-induced gas- group. A single independent study coordinator prepared the tric ulcers. randomization sequence, which was accomplished by using a block design with a block size of 4. Randomization of the block was conducted using a random-number chart. Methods Beginning on the third day after ESD, the patients in the ilaprazole group were administered ilaprazole 20 mg oral Study population tablets once a day for 56 days, and the patients in the rabe- prazole group were administered rabeprazole 20 mg oral Patients who underwent ESD for the treatment of gastric tablets once a day for 56 days. The enrolled patients under- adenoma or early gastric cancer from June 2015 to March went follow-up endoscopy at 4 weeks and 8 weeks after ESD 2018 at the Hallym University-Affiliated Hospitals, includ- to evaluate the degree and quality of ulcer healing. Adverse ing the Chuncheon, Kangdong, and Dongtan Sacred Heart events and drug compliance were evaluated at 4 weeks and Hospital were enrolled. Inclusion criteria were as follows: 8 weeks. The visit window was 1 week. Helicobacter pylori (1) 19 years of age or older; (2) pathologically diagnosed (H. pylori) infection was evaluated by histopathologic exam- gastric adenoma or cancer that was eligible for ESD [11, ination, rapid urease test (Pronto Dry New®; Medical Instru- 12]; and (3) agreed to participate and voluntarily provided ments Corp., Herford, Germany), and/or the 13C-urea breath informed consent. Exclusion criteria were as follows: (1) test (HeliFinder cap®; MediChems Corp., Seoul, Korea) 1 3 1378 Surgical Endoscopy (2019) 33:1376–1385 before performing the ESD. We defined H. pylori infection ulcer area − ulcer area at 4 or 8 weeks) × 100/initial ulcer as positive when at least one of the tests showed positivity. area]. The maximum diameter and the largest diameter All enrolled patients were asked to complete the modified perpendicular to the maximum diameter of the ulcer were Korean form of the Gastrointestinal Symptom Rating Scale measured using an endoscopic measuring device (M2-3U®; (KGSRS) to evaluate the change in clinical symptoms before Olympus Co., Ltd., Tokyo, Japan). Ulcerated areas were cal- and after performing ESD [14, 15]. KGSRS is a rating scale culated by multiplying these two diameters. The secondary consisting of 15 parameters and is widely used to assess outcomes were change in ulcer stage, quality of ulcer heal- abdominal symptoms in patients with peptic ulcers. ing, change in clinical symptoms, and whether healing was The study protocol adhered to the ethical guidelines delayed after ESD.