Article Search
검색
검색 팝업 닫기

Metrics

Help

  • 1. Aims and Scope

    Gut and Liver is an international journal of gastroenterology, focusing on the gastrointestinal tract, liver, biliary tree, pancreas, motility, and neurogastroenterology. Gut atnd Liver delivers up-to-date, authoritative papers on both clinical and research-based topics in gastroenterology. The Journal publishes original articles, case reports, brief communications, letters to the editor and invited review articles in the field of gastroenterology. The Journal is operated by internationally renowned editorial boards and designed to provide a global opportunity to promote academic developments in the field of gastroenterology and hepatology. +MORE

  • 2. Editorial Board

    Editor-in-Chief + MORE

    Editor-in-Chief
    Yong Chan Lee Professor of Medicine
    Director, Gastrointestinal Research Laboratory
    Veterans Affairs Medical Center, Univ. California San Francisco
    San Francisco, USA

    Deputy Editor

    Deputy Editor
    Jong Pil Im Seoul National University College of Medicine, Seoul, Korea
    Robert S. Bresalier University of Texas M. D. Anderson Cancer Center, Houston, USA
    Steven H. Itzkowitz Mount Sinai Medical Center, NY, USA
  • 3. Editorial Office
  • 4. Articles
  • 5. Instructions for Authors
  • 6. File Download (PDF version)
  • 7. Ethical Standards
  • 8. Peer Review

    All papers submitted to Gut and Liver are reviewed by the editorial team before being sent out for an external peer review to rule out papers that have low priority, insufficient originality, scientific flaws, or the absence of a message of importance to the readers of the Journal. A decision about these papers will usually be made within two or three weeks.
    The remaining articles are usually sent to two reviewers. It would be very helpful if you could suggest a selection of reviewers and include their contact details. We may not always use the reviewers you recommend, but suggesting reviewers will make our reviewer database much richer; in the end, everyone will benefit. We reserve the right to return manuscripts in which no reviewers are suggested.

    The final responsibility for the decision to accept or reject lies with the editors. In many cases, papers may be rejected despite favorable reviews because of editorial policy or a lack of space. The editor retains the right to determine publication priorities, the style of the paper, and to request, if necessary, that the material submitted be shortened for publication.

Search

Search

Year

to

Article Type

Original Article

Split Viewer

The Effect of Tegoprazan on the Treatment of Endoscopic Resection-Induced Artificial Ulcers: A Multicenter, Randomized, Active-Controlled Study

Byung-Wook Kim1 , Jong Jae Park2 , Hee Seok Moon3 , Wan Sik Lee4 , Ki-Nam Shim5 , Gwang Ho Baik6 , Yun Jeong Lim7 , Hang Lak Lee8 , Young Hoon Youn9 , Jun Chul Park10 , In-Kyung Sung11 , Hyunsoo Chung12 , Jeong Seop Moon13 , Gwang Ha Kim14 , Su Jin Hong15 , Hyuk Soon Choi16

1Department of Internal Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea; 2Division of Gastroenterology, Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea; 3Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon, Korea; 4Department of Internal Medicine, Chonnam National University Hwasun Hospital, Hwasun, Korea; 5Department of Internal Medicine, Ewha Womans University College of Medicine, Seoul, Korea; 6Department of Internal Medicine, Hallym University Chuncheon Sacred Heart Hospital, Hallym University College of Medicine, Chuncheon, Korea; 7Department of Internal Medicine, Dongguk University Ilsan Hospital, Dongguk University College of Medicine, Goyang, Korea; 8Department of Internal Medicine, Hanyang University Medical Center, Seoul, Korea; 9Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea; 10Department of Gastroenterology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea; 11Department of Internal Medicine, Konkuk University Medical Center, Konkuk University College of Medicine, Seoul, Korea; 12Department of Internal Medicine and Liver Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea; 13Department of Internal Medicine, Inje University Seoul Paik Hospital, Inje University College of Medicine, Seoul, Korea; 14Department of Internal Medicine, Pusan National University College of Medicine and Biomedical Research Institute, Pusan National University Hospital, Busan, Korea; 15Digestive Disease Center and Research Institute, Department of Internal Medicine, Soonchunhyang University College of Medicine, Bucheon, Korea; 16Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea

Correspondence to: Jong Jae Park
ORCID https://orcid.org/0000-0002-4642-5405
E-mail gi7pjj@korea.ac.kr

Received: June 25, 2023; Revised: August 18, 2023; Accepted: August 22, 2023

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Gut Liver 2024;18(2):257-264. https://doi.org/10.5009/gnl230242

Published online February 22, 2024, Published date March 15, 2024

Copyright © Gut and Liver.

Background/Aims: Tegoprazan is a novel potassium-competitive acid blocker that has beneficial effects on acid-related disorders such as gastroesophageal reflux and peptic ulcer diseases. This study aimed to validate the effect of tegoprazan on endoscopic submucosal dissection (ESD)-induced artificial ulcers.
Methods: Patients from 16 centers in Korea who underwent ESD for gastric neoplasia were enrolled. After ESD, pantoprazole was administered intravenously for 48 hours. The patients were randomly allocated to either the tegoprazan or esomeprazole group. Tegoprazan 50 mg or esomeprazole 40 mg were administered for 4 weeks, after which gastroscopic evaluation was performed. If the artificial ulcer had not healed, the same dose of tegoprazan or esomeprazole was administered for an additional 4 weeks, and a gastroscopic evaluation was performed.
Results: One hundred sixty patients were enrolled in this study. The healing rates of artificial ulcers at 4 weeks were 30.3% (23/76) and 22.1% (15/68) in the tegoprazan and esomeprazole groups, respectively (p=0.006). At 8 weeks after ESD, the cumulative ulcer healing rates were 73.7% (56/76) and 77.9% (53/68) in the tegoprazan and esomeprazole groups, respectively (p=0.210). Delayed bleeding occurred in two patients in the tegoprazan group (2.6%) and in one patient in the esomeprazole group (1.5%). Other adverse events were negligible in both groups.
Conclusions: Tegoprazan showed similar effects on post-ESD artificial ulcer healing in comparison with esomeprazole.

Keywords: Tegoprazan, Endoscopic resection, Endoscopic submucosal dissection, Gastric neoplasia, Multicenter prospective randomized study

Acid-reducing agents, such as proton pump inhibitors (PPIs), are administered after endoscopic submucosal dissection (ESD) for gastric neoplasia and non-ampullary duodenal tumors to avoid adverse events such as delayed bleeding.1-3 PPIs should be administered before meal; however, approximately half the patients do not take PPIs before breakfast,4 thus limiting their effects. Potassium-competitive acid blockers (P-CABs), which are novel acid-reducing agents, have been introduced to overcome the limitations of PPIs. P-CABs can be taken regardless of the meal times.

Vonoprazan, one of the P-CABs developed in Japan, has shown some benefits over PPIs in Helicobacter pylori eradication and the treatment of peptic ulcer diseases and gastroesophageal reflux diseases.5-7 Vonoprazan was also as effective as PPIs in preventing bleeding after ESD and healing of artificial ulcers after ESD for gastric neoplasia.8,9 Tegoprazan is a novel P-CAB developed in Korea that suppresses gastric acid secretion faster and more potently than PPIs.10 It is as effective as PPIs in the treatment of gastric ulcers and in H. pylori eradication.11,12 Tegoprazan is also effective in the treatment of gastroesophageal reflux diseases.13,14 However, the effect of tegoprazan in healing artificial ulcers after ESD is yet to be elucidated. This study aimed to evaluate the efficacy and safety of tegoprazan in the treatment of artificial ulcers after ESD in comparison to those of PPIs.

1. Study design and data management

This study was a multicenter, randomized, double-blind, active-controlled, non-inferiority trial comparing tegoprazan (50 mg/day) and esomeprazole (40 mg/day). The study protocol was approved by the Korean Ministry of Food and Drug Safety (Registration number 32524) and the institutional review boards of each institution including Korea University Guro Hospital (IRB number: 2020GR0069). This study followed the Declaration of Helsinki and the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use‐Good Clinical Practice guidelines. Informed consent was obtained from all patients prior to enrollment. This study was registered at the Korean Disease Control and Prevention Agency registration site, Clinical Research Information Service (KCT0005470).

Drug distribution was determined according to the drug randomization number generated by an interactive web response system (cubeIWRS; CRScube Inc., Seoul, Korea). A double‐dummy method, using matching tegoprazan 50 mg and esomeprazole 40 mg, was employed to ensure that the study was double-blinded with key codes kept off-site by an external data manager. All medications were provided in sealed boxes and supplied by the medication supervisor to ensure blinded allocation. Blinded data were securely stored and could only be accessed by authorized personnel. All authors had access to the study data and reviewed and approved the final manuscript.

2. Patients

This study was performed at 16 centers in Korea. Inclusion criteria were as follows: patients aged 20 to 75 years who were diagnosed histologically and endoscopically with (1) gastric adenoma; (2) differentiated type gastric adenocarcinoma without ulcer; (3) differentiated type gastric adenocarcinoma with ulcer not involving submucosa less than 3.0 cm; (4) differentiated type gastric adenocarcinoma infiltrating submucosa less than 500 μm without ulcer less than 3.0 cm; and (5) undifferentiated type gastric adenocarcinoma not involving the submucosa without ulcer less than 2.0 cm. Exclusion criteria were as follows: (1) the size of artificial ulcer after ESD was over 4.0 cm; (2) overt bleeding or perforation after ESD; (3) past history of upper gastrointestinal tract surgery; (4) esophageal stricture, gastric outlet obstruction, or active peptic ulcer; (5) follow-up gastroscopy not available; (6) past history of adverse events to tegoprazan, PPI, or benzimidazole; (7) patients who were taking atazanavir, nelfinavir, rilpivirine, terfenadine, cisapride, pimozide, or astemizole; (8) pregnant or nursing women; (9) patients with uncontrolled cardiopulmonary diseases, renal diseases, liver diseases, neurologic diseases, or endocrine diseases including diabetes; (10) patients with cognition disorder or mental retardation; (11) patients who were taking anti-depressants, anxiolytics, or anti-psychotics; (12) patients who took PPI or H2 receptor antagonists within 2 weeks before ESD; (13) patients who were taking steroids, nonsteroidal anti-inflammatory drugs, aspirin, anti-platelet agents, or anticoagulants during the study period; (14) patients with aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma-glutamyl transferase, or bilirubin over 2 times the reference value; or (15) patients with blood urea nitrogen or creatinine over 1.5 times the reference value. Fasting serum gastrin level was checked on day zero and 4 and 8 weeks after ESD.

3. Endoscopic submucosal dissection

ESD was performed under conscious sedation. Sedative drugs were chosen by each endoscopist’s preference. A mixture of 0.001% epinephrine, 0.1% indigo carmine, and normal saline was injected into submucosal layer and mucosal cutting followed by submucosal dissection was performed using each endoscopist’s preference of knives. Hemorrhage during the procedure was controlled with hemostatic forceps. After ESD, the size of artificial ulcer was measured using biopsy forceps.

4. Administration of tegoprazan or esomeprazole

Immediately after ESD, a bolus of 80 mg pantoprazole was administered intravenously, followed by 8 mg per hour for 48 hours. Eligible patients were randomly assigned in a 1:1 ratio to receive either tegoprazan or esomeprazole during this period. Two days after ESD, the patients were instructed to take one tablet of 50 mg tegoprazan with one placebo esomeprazole tablet (tegoprazan group) or one placebo tegoprazan tablet with one tablet of 40 mg esomeprazole (esomeprazole group) once daily before breakfast for 4 weeks. Gastroscopic evaluation was performed 4 weeks after ESD. When an artificial ulcer was found in the active or healing stage according to Sakita-Miwa’s classification on gastroscopy 4 weeks after ESD, 50 mg tegoprazan with placebo or 40 mg esomeprazole with placebo was administered 4 weeks more. In these patients, gastroscopic evaluation was performed again 8 weeks after ESD. The study process is illustrated in Fig. 1.

Figure 1.A diagram indicating the progression of the study. IV, intravenous; ESD, endoscopic submucosal dissection.

5. Outcomes

The primary endpoint of this study was the healing rates of ESD-induced artificial ulcers at 4 and 8 weeks. The secondary endpoints were as follows: (1) healing rates of ESD-induced artificial ulcers at 4 weeks and 8 weeks; (2) change in ulcer size; and (3) the incidence of delayed bleeding. Healing of ESD-induced artificial ulcer was defined as the complete closure of the mucosal defect. The ulcer size was measured as follows: the mucosal defect after ESD was considered elliptical, and the area was calculated by multiplying the long axis radius and the short axis radius, followed by multiplying π, and expressed in mm2. The shrinkage rates of the artificial ulcers at 4 and 8 weeks were also compared as an exploratory endpoint. The shrinkage rate of artificial ulcers was calculated as the ratio of ulcer size at 4 and 8 weeks to the ulcer size immediately after ESD. The size of the artificial ulcer was measured using opening biopsy forceps. Delayed bleeding was defined by overt hemorrhage signs such as hematemesis or melena over 24 hours after initiating either tegoprazan or esomeprazole along with a decrease in hemoglobin level of over 2.0 g/dL.

Safety was evaluated using vital signs (blood pressure, heart rate, and body temperature), physical examination, serum gastrin level, and incidence of treatment-emergent adverse events (TEAEs). A TEAE was defined as an adverse event that occurred after the participant received the study drug. TEAEs were categorized by severity and relativity and compared between the treatment groups. Adverse events were analyzed in the safety set.

6. Statistical analysis

For sample size calculation, the healing rate of artificial ulcers at 8 weeks was assumed to be 95.5% for tegoprazan and esomeprazole, with a non-inferiority margin of –10% and a power of 80% at a significant level of 2.5% (one-sided).15 While a direct comparison between vonoprazan and tegoprazan for artificial ulcer healing is lacking, an indirect comparison was conducted using data from reports. Specifically, it was found that vonoprazan exhibited comparable effectiveness to lansoprazole in healing gastric ulcers (93.5% for vonoprazan and 93.8% for lansoprazole), and similarly, tegoprazan demonstrated comparable efficacy to lansoprazole in gastric ulcer healing (95.0% for tegoprazan and 95.7% for lansoprazole).6,11 The total sample size was 160 subjects, with 80 patients per treatment group, considering a 15% drop-out.

For continuous variables, the values are provided as the number of subjects, mean, standard deviation, median, minimum and maximum. For categorical variables, the values are presented as frequencies and percentages. The non-inferiority test of tegoprazan versus esomeprazole in healing rate was to be declared if the lower bound of the two-sided 95% confidence interval for the difference between the two arms was greater than the non-inferiority margin, –10%. Continuous variables were compared by the Student t-test or Wilcoxon rank-sum test depending on whether the normality assumption was satisfied. Categorical variables were compared by the chi-square test or Fisher exact test depending on whether 20% or more of cells with an expected frequency of 5 or less were found.

All two-sided statistical tests were performed at a significance level of 5% unless otherwise specified. Statistical analyses were performed using SAS 9.4 (SAS Institution Inc., Cary, NC, USA).

1. Baseline characteristics

Among the 167 patients with an artificial ulcer after ESD who were screened, three were ineligible based on the inclusion/exclusion criteria, and four withdrew their consent. These participants were considered to have screening failure, and the remaining 160 patients were randomized in a 1:1 ratio to one of the two treatment arms: tegoprazan or esomeprazole. Among the 160 randomized patients, 16 (10.0%) were discontinued from the study due to the lack of viable data (n=10, 6.3%), violation of an inclusion/exclusion criteria (n=5, 3.1%), or withdrawal of consent before exposure to the study drug (n=1, 0.6%) (Fig. 2). The baseline characteristics of the patients are summarized in Table 1. No significant differences in baseline characteristics were observed between the treatment groups.

Figure 2.Disposition of patients included in this study.


Baseline Characteristic of Patients in the Full Analysis Set


CharacteristicTegoprazan group (n=76)Esomeprazole group (n=68)
Sex, No. (%)
Male57 (75.0)46 (67.7)
Female19 (25.0)22 (32.3)
Age, mean±SD, yr62.0±7.463.0±7.8
Social history, No. (%)
Smoking16 (21.1)9 (13.2)
Alcohol29 (38.2)18 (26.5)
Pre-procedural histology, No. (%)
Adenoma, low grade dysplasia41 (54.0)37 (54.4)
Adenoma, high grade dysplasia13 (17.1)13 (19.1)
Differentiated adenocarcinoma17 (22.4)17 (25.0)
Undifferentiated adenocarcinoma2 (2.6)1 (1.5)
Mixed3 (4.0)0
Ulcer size immediately after ESD, mean±SD, mm2507.1±277.7562.9±324.8

ESD, endoscopic submucosal dissection.



2. Ulcer healing

The healing rates of artificial ulcers at 4 weeks were 30.3% (23/76) and 22.1% (15/68) in tegoprazan group and in esomeprazole group, respectively. The percentage difference between the tegoprazan group and esomeprazole group was <–10% (95% confidence interval, –6.07 to 22.48), which confirmed the non-inferiority of the tegoprazan group in comparison to the esomeprazole group. At 8 weeks after ESD, the cumulative healing rates of artificial ulcers were 73.7% (56/76) and 77.9% (53/68) in tegoprazan and esomeprazole groups, respectively (95% confidence interval, –18.23 to 9.71). The results are summarized in Table 2. Immediately after ESD, the ulcer size was 508.18±274.10 mm2 and 585.63±309.72 mm2 in tegoprazan group and esomeprazole groups, respectively (p=0.180). Four weeks after ESD, the ulcer size was 51.63±75.06 mm2 and 60.26±79.51 mm2 in tegoprazan and esomeprazole groups, respectively (p=0.400). Eight weeks after ESD, the ulcer size was 2.64±7.93 mm2 and 8.19±41.68 mm2 in tegoprazan and esomeprazole groups, respectively (p=0.761). The two groups showed no difference in changes in ulcer stages. A summary of the changes in ulcer stages can be found in Table 3.


Cumulative Healing Rates of Artificial Ulcers


VariableHealing of the artificial ulcer (%)Difference, % (95% CI)p-value
4 wk8.20 (–6.07 to 22.48)0.006
Tegoprazan group30.3 (23/76)
Esomeprazole group22.1 (15/68)
8 wk–4.20 (–18.23 to 9.71)0.210
Tegoprazan group73.7 (56/76)
Esomeprazole group77.9 (53/68)

Data are presented as percentages with number of subjects in parentheses, confidence interval (CI), non-inferiority margin –10%.




Changes in Ulcer Stages at 4 and 8 Weeks after ESD


Tegoprazan
group (n=74)
Esomeprazole
group (n=67)
4 wk after ESD
A1/A28 (10.8)10 (14.9)
H1/H243 (58.1)42 (62.7)
S1/S223 (31.1)15 (22.4)
8 wk after ESD
A1/A21 (1.4)2 (3.0)
H1/H217 (23.0)12 (17.9)
S1/S256 (75.7)53 (79.1)

Data are presented as number (%).

ESD, endoscopic submucosal dissection.



At 4 weeks after ESD, the shrinkage rates of artificial ulcers were 85.6% in tegoprazan group and 85.0% in esomeprazole group, respectively (p=0.897). At 8 weeks after ESD, the shrinkage rates of artificial ulcers were 94.9% and 94.2% in the tegoprazan and esomeprazole groups, respectively (p=0.842).

3. Delayed bleeding and safety

Delayed bleeding occurred in two patients (2.6%) from the tegoprazan group and in one patient (1.5%) from the esomeprazole group (p=1.000). In all cases, melena was the first sign of delayed bleeding. One patient from the tegoprazan group experienced melena 9 days after ESD, and another patient from the same group had melena 14 days after ESD. One patient from the esomeprazole group had melena 10 days after ESD. Gastroscopy confirmed bleeding from the ESD site, with Forrest Ib observed in one patient from the esomeprazole group and Forrest IIa in two patients from the tegoprazan group. Delayed bleeding was successfully managed using endoscopic hemostasis in all the patients. Hemoglobin levels dropped from 2.1 g/dL to 3.2 g/dL.

Safety analysis was performed in 159 patients who received ≥1 dose of the study drug and underwent ≥1 safety assessment in this clinical trial. Among the 159 patients, 15 cases of TEAEs were reported in 12 patients. In the esomeprazole group only, one nausea, urticarial, and skin rash were reported as drug-related TEAEs (n=1, 1.28%).

4. Serum gastrin level

The baseline serum gastrin levels were 94.99±105.78 pg/mL and 100.81±119.89 pg/mL for the tegoprazan and esomeprazole groups, respectively (Fig. 3). The serum gastrin levels were 82.14±70.5 pg/mL and 86.52±72.57 pg/mL at 4 weeks and 99.22±86.24 pg/mL and 96.21±81.65 pg/mL at 8 weeks for the tegoprazan and esomeprazole groups, respectively. The changes in serum gastrin levels did not differ significantly between the tegoprazan and esomeprazole groups.

Figure 3.Changes in the serum gastrin level before and after tegoprazan and esomeprazole administration.

In this study, we found that 50 mg of tegoprazan was not inferior to 40 mg of esomeprazole in treating artificial ulcers after ESD for gastric neoplasia. The healing rate of artificial ulcers at 4 weeks after ESD was higher in the tegoprazan group than in the esomeprazole group, whereas cumulative healing rate at 8 weeks after ESD did not show a significant difference between the two groups. From these results, it is plausible that tegoprazan has a more potent acid-suppressive effect than esomeprazole; therefore, the healing process after ESD progressed rapidly in the tegoprazan group. Some studies have observed that vonoprazan, another P-CAB, was superior to PPIs in the healing of artificial ulcers after ESD for gastric neoplasia, indicating similarities with our study.9,16 However, it is still uncertain whether P-CAB is superior to PPI in the healing of artificial ulcers after ESD for gastric neoplasia. A systematic review and meta-analysis showed that vonoprazan was superior to PPI at 4 weeks after ESD,17 whereas another recent systematic review and meta-analysis showed that there was no difference between vonoprazan and PPI.18

The healing rate of artificial ulcers at 4 weeks after administration of P-CABs or PPIs was reported to range from less than 10% to over 90% in various studies.16,19,20 This large variation among the studies might result from interpretation of H3 stage ulcers according to the Sakita-Miwa classification.21 In this study, the healing rates of artificial ulcers were 30.3% in the tegoprazan group and 22.1% in the esomeprazole group at 4 weeks after ESD. This result was similar to a recent study comparing the efficacy of vonoprazan and lansoprazole treatment for artificial ulcers.19 We strictly interpreted the ulcer stages and even minute ulcer bases were classified as healing stages. Additionally, the shrinkage rates of artificial ulcers should not be misinterpreted as complete healing. At 8 weeks after ESD, the artificial ulcers healed by more than 70% in both groups in this study. Considering these results, acid-reducing agents should be administered at least 8 weeks after ESD. Since cumulative ulcer healing rates at 8 weeks after ESD were not 100% in both groups, an adequate duration of acid-reducing agents used after ESD for gastric neoplasia should be elucidated in further studies.

Our study did not show any difference in delayed bleeding rates between the tegoprazan and esomeprazole groups. Delayed bleeding was not the main outcome of our study, and the number of patients enrolled in this study might not have been sufficient. Considering that most delayed bleeding occurs within a week after ESD,22 delayed bleeding may be preventable with more potent acid suppression. A large-scale prospective study is needed to elucidate the effect of tegoprazan on delayed bleeding.

Although P-CABs can overcome some of the unmet needs of PPIs, they still have some limitations in clinical practice. It is well known that serum gastrin levels might increase after administration of P-CABs.23 Tegoprazan has a different chemical structure than vonoprazan and revaprazan. There were no changes in the serum gastrin levels in either group in this study. This was similar to the results of previous studies.11,24 Therefore, tegoprazan might be safely administered for up to 8 weeks. Further studies with large numbers of patients are warranted.

The strength of this study is that it is a multicenter, randomized, double-blind, active-controlled study. Despite this strength, this is a non-inferiority study, and it cannot be concluded that 50 mg of tegoprazan is superior to 40 mg of esomeprazole in the healing of artificial ulcers after ESD for gastric neoplasia. Another limitation is that intravenous pantoprazole was administered for 48 hours before starting oral tegoprazan or esomeprazole because tegoprazan cannot be administered intravenously. Therefore, the immediate effect of tegoprazan after ESD was not evaluated in this study. Hemoglobin levels were not checked within 2 weeks after ESD, which may lead to underestimation of delayed bleeding occurrences.

In conclusion, this is the first study to investigate the effect of tegoprazan on the healing of artificial ulcers after ESD for gastric neoplasia. Tegoprazan showed a similar effect on post-ESD artificial ulcer healing in comparison to esomeprazole, constituting that tegoprazan can be a new option for the treatment of ESD-induced artificial ulcers.

This study was supported by HK Inno.N Corp. HK Inno.N provided financial support and study drug.

This study was supported by HK Inno.N Corp. HK Inno.N provided financial support and study drug. However, no role in the design of this study, study conduct, data analysis, and interpretation of the data.

B.W.K. and G.H.K. are editorial board members of the journal but were not involved in the peer reviewer selection, evaluation, or decision process of this article. No other potential conflicts of interest relevant to this article were reported.

Study concept and design: J.J.P. Data acquisition: B.W.K., J.J.P., H.S.M., W.S.L., K.N.S., G.H.B., Y.J.L., H.L.L., Y.H.Y., J.C.P., I.K.S., H.C., J.S.M., G.H.K., S.J.H., H.S.C. Data analysis and interpretation: B.W.K. Drafting of the manuscript: B.W.K. Critical revision of the manuscript for important intellectual content: J.J.P., H.S.M., W.S.L., K.N.S., G.H.B., Y.J.L., H.L.L., Y.H.Y., J.C.P., I.K.S., H.C., J.S.M., G.H.K., S.J.H., H.S.C. Statistical analysis: B.W.K. Obtained funding: J.J.P. Study supervision: J.J.P.

  1. Uedo N, Takeuchi Y, Yamada T, et al. Effect of a proton pump inhibitor or an H2-receptor antagonist on prevention of bleeding from ulcer after endoscopic submucosal dissection of early gastric cancer: a prospective randomized controlled trial. Am J Gastroenterol 2007;102:1610-1616.
    Pubmed CrossRef
  2. Ye BD, Cheon JH, Choi KD, et al. Omeprazole may be superior to famotidine in the management of iatrogenic ulcer after endoscopic mucosal resection: a prospective randomized controlled trial. Aliment Pharmacol Ther 2006;24:837-843.
    Pubmed CrossRef
  3. An JY, Kim BW, Kim JS, Park JM, Kim TH, Lee J. The use of endoscopic clipping in preventing delayed complications after endoscopic resection for superficial non-ampullary duodenal tumors. Clin Endosc 2021;54:563-569.
    Pubmed KoreaMed CrossRef
  4. Chey WD, Mody RR, Wu EQ, et al. Treatment patterns and symptom control in patients with GERD: US community-based survey. Curr Med Res Opin 2009;25:1869-1878.
    Pubmed CrossRef
  5. Jung YS, Kim EH, Park CH. Systematic review with meta-analysis: the efficacy of vonoprazan-based triple therapy on Helicobacter pylori eradication. Aliment Pharmacol Ther 2017;46:106-114.
    Pubmed CrossRef
  6. Miwa H, Uedo N, Watari J, et al. Randomised clinical trial: efficacy and safety of vonoprazan vs. lansoprazole in patients with gastric or duodenal ulcers: results from two phase 3, non-inferiority randomised controlled trials. Aliment Pharmacol Ther 2017;45:240-252.
    Pubmed KoreaMed CrossRef
  7. Oshima T, Arai E, Taki M, et al. Randomised clinical trial: vonoprazan versus lansoprazole for the initial relief of heartburn in patients with erosive oesophagitis. Aliment Pharmacol Ther 2019;49:140-146.
    Pubmed CrossRef
  8. Hamada K, Uedo N, Tonai Y, et al. Efficacy of vonoprazan in prevention of bleeding from endoscopic submucosal dissection-induced gastric ulcers: a prospective randomized phase II study. J Gastroenterol 2019;54:122-130.
    Pubmed CrossRef
  9. Tsuchiya I, Kato Y, Tanida E, et al. Effect of vonoprazan on the treatment of artificial gastric ulcers after endoscopic submucosal dissection: prospective randomized controlled trial. Dig Endosc 2017;29:576-583.
    Pubmed CrossRef
  10. Takahashi N, Take Y. Tegoprazan, a novel potassium-competitive acid blocker to control gastric acid secretion and motility. J Pharmacol Exp Ther 2018;364:275-286.
    Pubmed CrossRef
  11. Cho YK, Choi MG, Choi SC, et al. Randomised clinical trial: tegoprazan, a novel potassium-competitive acid blocker, or lansoprazole in the treatment of gastric ulcer. Aliment Pharmacol Ther 2020;52:789-797.
    Pubmed KoreaMed CrossRef
  12. Choi YJ, Lee YC, Kim JM, et al. Triple therapy-based on tegoprazan, a new potassium-competitive acid blocker, for first-line treatment of Helicobacter pylori infection: a randomized, double-blind, phase III, clinical trial. Gut Liver 2022;16:535-546.
    Pubmed KoreaMed CrossRef
  13. Lee KJ, Son BK, Kim GH, et al. Randomised phase 3 trial: tegoprazan, a novel potassium-competitive acid blocker, vs. esomeprazole in patients with erosive oesophagitis. Aliment Pharmacol Ther 2019;49:864-872.
    Pubmed KoreaMed CrossRef
  14. Kim SH, Cho KB, Chun HJ, et al. Randomised clinical trial: comparison of tegoprazan and placebo in non-erosive reflux disease. Aliment Pharmacol Ther 2021;54:402-411.
    Pubmed KoreaMed CrossRef
  15. Takahashi K, Sato Y, Kohisa J, et al. Vonoprazan 20 mg vs lansoprazole 30 mg for endoscopic submucosal dissection-induced gastric ulcers. World J Gastrointest Endosc 2016;8:716-722.
    Pubmed KoreaMed CrossRef
  16. Maruoka D, Arai M, Kasamatsu S, et al. Vonoprazan is superior to proton pump inhibitors in healing artificial ulcers of the stomach post-endoscopic submucosal dissection: a propensity score-matching analysis. Dig Endosc 2017;29:57-64.
    Pubmed CrossRef
  17. Kang H, Kim BJ, Choi G, Kim JG. Vonoprazan versus proton pump inhibitors for the management of gastric endoscopic submucosal dissection-induced artificial ulcer: a systematic review with meta-analysis. Medicine (Baltimore) 2019;98:e15860.
    Pubmed KoreaMed CrossRef
  18. Miao T, Zhang Y, Bai L, Yang X, Wen X. Vonoprazan vs. lansoprazole for the treatment of endoscopic submucosal dissection induced gastric ulcer: a systematic review and meta-analysis. Rev Esp Enferm Dig 2023;115:168-174.
    Pubmed CrossRef
  19. Kawai D, Takenaka R, Ishiguro M, et al. Vonoprazan versus lansoprazole in the treatment of artificial gastric ulcers after endoscopic submucossal dissection: a randomized, open-label trial. BMC Gastroenterol 2021;21:236.
    Pubmed KoreaMed CrossRef
  20. Ishii Y, Yamada H, Sato T, et al. Effects of vonoprazan compared with esomeprazole on the healing of artificial postendoscopic submucosal dissection ulcers: a prospective, multicenter, two-arm, randomized controlled trial. Gastroenterol Res Pract 2018;2018:1615092.
    Pubmed KoreaMed CrossRef
  21. Sakita T, Fukutomi H. Endoscopic diagnosis. In: Yoshitoshi Y, ed. All about gastric and duodenal ulcer. Tokyo: Nankodo, 1972:200-211.
  22. Choi IJ, Lee NR, Kim SG, et al. Short-term outcomes of endoscopic submucosal dissection in patients with early gastric cancer: a prospective multicenter cohort study. Gut Liver 2016;10:739-748.
    Pubmed KoreaMed CrossRef
  23. Jenkins H, Sakurai Y, Nishimura A, et al. Randomised clinical trial: safety, tolerability, pharmacokinetics and pharmacodynamics of repeated doses of TAK-438 (vonoprazan), a novel potassium-competitive acid blocker, in healthy male subjects. Aliment Pharmacol Ther 2015;41:636-648.
    Pubmed KoreaMed CrossRef
  24. He J, Cao G, Yu J, et al. Safety, tolerability and pharmacokinetics of single ascending and multiple oral doses of tegoprazan in healthy Chinese subjects. Clin Drug Investig 2021;41:89-97.
    Pubmed CrossRef

Article

Original Article

Gut and Liver 2024; 18(2): 257-264

Published online March 15, 2024 https://doi.org/10.5009/gnl230242

Copyright © Gut and Liver.

The Effect of Tegoprazan on the Treatment of Endoscopic Resection-Induced Artificial Ulcers: A Multicenter, Randomized, Active-Controlled Study

Byung-Wook Kim1 , Jong Jae Park2 , Hee Seok Moon3 , Wan Sik Lee4 , Ki-Nam Shim5 , Gwang Ho Baik6 , Yun Jeong Lim7 , Hang Lak Lee8 , Young Hoon Youn9 , Jun Chul Park10 , In-Kyung Sung11 , Hyunsoo Chung12 , Jeong Seop Moon13 , Gwang Ha Kim14 , Su Jin Hong15 , Hyuk Soon Choi16

1Department of Internal Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea; 2Division of Gastroenterology, Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea; 3Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon, Korea; 4Department of Internal Medicine, Chonnam National University Hwasun Hospital, Hwasun, Korea; 5Department of Internal Medicine, Ewha Womans University College of Medicine, Seoul, Korea; 6Department of Internal Medicine, Hallym University Chuncheon Sacred Heart Hospital, Hallym University College of Medicine, Chuncheon, Korea; 7Department of Internal Medicine, Dongguk University Ilsan Hospital, Dongguk University College of Medicine, Goyang, Korea; 8Department of Internal Medicine, Hanyang University Medical Center, Seoul, Korea; 9Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea; 10Department of Gastroenterology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea; 11Department of Internal Medicine, Konkuk University Medical Center, Konkuk University College of Medicine, Seoul, Korea; 12Department of Internal Medicine and Liver Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea; 13Department of Internal Medicine, Inje University Seoul Paik Hospital, Inje University College of Medicine, Seoul, Korea; 14Department of Internal Medicine, Pusan National University College of Medicine and Biomedical Research Institute, Pusan National University Hospital, Busan, Korea; 15Digestive Disease Center and Research Institute, Department of Internal Medicine, Soonchunhyang University College of Medicine, Bucheon, Korea; 16Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea

Correspondence to:Jong Jae Park
ORCID https://orcid.org/0000-0002-4642-5405
E-mail gi7pjj@korea.ac.kr

Received: June 25, 2023; Revised: August 18, 2023; Accepted: August 22, 2023

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background/Aims: Tegoprazan is a novel potassium-competitive acid blocker that has beneficial effects on acid-related disorders such as gastroesophageal reflux and peptic ulcer diseases. This study aimed to validate the effect of tegoprazan on endoscopic submucosal dissection (ESD)-induced artificial ulcers.
Methods: Patients from 16 centers in Korea who underwent ESD for gastric neoplasia were enrolled. After ESD, pantoprazole was administered intravenously for 48 hours. The patients were randomly allocated to either the tegoprazan or esomeprazole group. Tegoprazan 50 mg or esomeprazole 40 mg were administered for 4 weeks, after which gastroscopic evaluation was performed. If the artificial ulcer had not healed, the same dose of tegoprazan or esomeprazole was administered for an additional 4 weeks, and a gastroscopic evaluation was performed.
Results: One hundred sixty patients were enrolled in this study. The healing rates of artificial ulcers at 4 weeks were 30.3% (23/76) and 22.1% (15/68) in the tegoprazan and esomeprazole groups, respectively (p=0.006). At 8 weeks after ESD, the cumulative ulcer healing rates were 73.7% (56/76) and 77.9% (53/68) in the tegoprazan and esomeprazole groups, respectively (p=0.210). Delayed bleeding occurred in two patients in the tegoprazan group (2.6%) and in one patient in the esomeprazole group (1.5%). Other adverse events were negligible in both groups.
Conclusions: Tegoprazan showed similar effects on post-ESD artificial ulcer healing in comparison with esomeprazole.

Keywords: Tegoprazan, Endoscopic resection, Endoscopic submucosal dissection, Gastric neoplasia, Multicenter prospective randomized study

INTRODUCTION

Acid-reducing agents, such as proton pump inhibitors (PPIs), are administered after endoscopic submucosal dissection (ESD) for gastric neoplasia and non-ampullary duodenal tumors to avoid adverse events such as delayed bleeding.1-3 PPIs should be administered before meal; however, approximately half the patients do not take PPIs before breakfast,4 thus limiting their effects. Potassium-competitive acid blockers (P-CABs), which are novel acid-reducing agents, have been introduced to overcome the limitations of PPIs. P-CABs can be taken regardless of the meal times.

Vonoprazan, one of the P-CABs developed in Japan, has shown some benefits over PPIs in Helicobacter pylori eradication and the treatment of peptic ulcer diseases and gastroesophageal reflux diseases.5-7 Vonoprazan was also as effective as PPIs in preventing bleeding after ESD and healing of artificial ulcers after ESD for gastric neoplasia.8,9 Tegoprazan is a novel P-CAB developed in Korea that suppresses gastric acid secretion faster and more potently than PPIs.10 It is as effective as PPIs in the treatment of gastric ulcers and in H. pylori eradication.11,12 Tegoprazan is also effective in the treatment of gastroesophageal reflux diseases.13,14 However, the effect of tegoprazan in healing artificial ulcers after ESD is yet to be elucidated. This study aimed to evaluate the efficacy and safety of tegoprazan in the treatment of artificial ulcers after ESD in comparison to those of PPIs.

MATERIALS AND METHODS

1. Study design and data management

This study was a multicenter, randomized, double-blind, active-controlled, non-inferiority trial comparing tegoprazan (50 mg/day) and esomeprazole (40 mg/day). The study protocol was approved by the Korean Ministry of Food and Drug Safety (Registration number 32524) and the institutional review boards of each institution including Korea University Guro Hospital (IRB number: 2020GR0069). This study followed the Declaration of Helsinki and the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use‐Good Clinical Practice guidelines. Informed consent was obtained from all patients prior to enrollment. This study was registered at the Korean Disease Control and Prevention Agency registration site, Clinical Research Information Service (KCT0005470).

Drug distribution was determined according to the drug randomization number generated by an interactive web response system (cubeIWRS; CRScube Inc., Seoul, Korea). A double‐dummy method, using matching tegoprazan 50 mg and esomeprazole 40 mg, was employed to ensure that the study was double-blinded with key codes kept off-site by an external data manager. All medications were provided in sealed boxes and supplied by the medication supervisor to ensure blinded allocation. Blinded data were securely stored and could only be accessed by authorized personnel. All authors had access to the study data and reviewed and approved the final manuscript.

2. Patients

This study was performed at 16 centers in Korea. Inclusion criteria were as follows: patients aged 20 to 75 years who were diagnosed histologically and endoscopically with (1) gastric adenoma; (2) differentiated type gastric adenocarcinoma without ulcer; (3) differentiated type gastric adenocarcinoma with ulcer not involving submucosa less than 3.0 cm; (4) differentiated type gastric adenocarcinoma infiltrating submucosa less than 500 μm without ulcer less than 3.0 cm; and (5) undifferentiated type gastric adenocarcinoma not involving the submucosa without ulcer less than 2.0 cm. Exclusion criteria were as follows: (1) the size of artificial ulcer after ESD was over 4.0 cm; (2) overt bleeding or perforation after ESD; (3) past history of upper gastrointestinal tract surgery; (4) esophageal stricture, gastric outlet obstruction, or active peptic ulcer; (5) follow-up gastroscopy not available; (6) past history of adverse events to tegoprazan, PPI, or benzimidazole; (7) patients who were taking atazanavir, nelfinavir, rilpivirine, terfenadine, cisapride, pimozide, or astemizole; (8) pregnant or nursing women; (9) patients with uncontrolled cardiopulmonary diseases, renal diseases, liver diseases, neurologic diseases, or endocrine diseases including diabetes; (10) patients with cognition disorder or mental retardation; (11) patients who were taking anti-depressants, anxiolytics, or anti-psychotics; (12) patients who took PPI or H2 receptor antagonists within 2 weeks before ESD; (13) patients who were taking steroids, nonsteroidal anti-inflammatory drugs, aspirin, anti-platelet agents, or anticoagulants during the study period; (14) patients with aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma-glutamyl transferase, or bilirubin over 2 times the reference value; or (15) patients with blood urea nitrogen or creatinine over 1.5 times the reference value. Fasting serum gastrin level was checked on day zero and 4 and 8 weeks after ESD.

3. Endoscopic submucosal dissection

ESD was performed under conscious sedation. Sedative drugs were chosen by each endoscopist’s preference. A mixture of 0.001% epinephrine, 0.1% indigo carmine, and normal saline was injected into submucosal layer and mucosal cutting followed by submucosal dissection was performed using each endoscopist’s preference of knives. Hemorrhage during the procedure was controlled with hemostatic forceps. After ESD, the size of artificial ulcer was measured using biopsy forceps.

4. Administration of tegoprazan or esomeprazole

Immediately after ESD, a bolus of 80 mg pantoprazole was administered intravenously, followed by 8 mg per hour for 48 hours. Eligible patients were randomly assigned in a 1:1 ratio to receive either tegoprazan or esomeprazole during this period. Two days after ESD, the patients were instructed to take one tablet of 50 mg tegoprazan with one placebo esomeprazole tablet (tegoprazan group) or one placebo tegoprazan tablet with one tablet of 40 mg esomeprazole (esomeprazole group) once daily before breakfast for 4 weeks. Gastroscopic evaluation was performed 4 weeks after ESD. When an artificial ulcer was found in the active or healing stage according to Sakita-Miwa’s classification on gastroscopy 4 weeks after ESD, 50 mg tegoprazan with placebo or 40 mg esomeprazole with placebo was administered 4 weeks more. In these patients, gastroscopic evaluation was performed again 8 weeks after ESD. The study process is illustrated in Fig. 1.

Figure 1. A diagram indicating the progression of the study. IV, intravenous; ESD, endoscopic submucosal dissection.

5. Outcomes

The primary endpoint of this study was the healing rates of ESD-induced artificial ulcers at 4 and 8 weeks. The secondary endpoints were as follows: (1) healing rates of ESD-induced artificial ulcers at 4 weeks and 8 weeks; (2) change in ulcer size; and (3) the incidence of delayed bleeding. Healing of ESD-induced artificial ulcer was defined as the complete closure of the mucosal defect. The ulcer size was measured as follows: the mucosal defect after ESD was considered elliptical, and the area was calculated by multiplying the long axis radius and the short axis radius, followed by multiplying π, and expressed in mm2. The shrinkage rates of the artificial ulcers at 4 and 8 weeks were also compared as an exploratory endpoint. The shrinkage rate of artificial ulcers was calculated as the ratio of ulcer size at 4 and 8 weeks to the ulcer size immediately after ESD. The size of the artificial ulcer was measured using opening biopsy forceps. Delayed bleeding was defined by overt hemorrhage signs such as hematemesis or melena over 24 hours after initiating either tegoprazan or esomeprazole along with a decrease in hemoglobin level of over 2.0 g/dL.

Safety was evaluated using vital signs (blood pressure, heart rate, and body temperature), physical examination, serum gastrin level, and incidence of treatment-emergent adverse events (TEAEs). A TEAE was defined as an adverse event that occurred after the participant received the study drug. TEAEs were categorized by severity and relativity and compared between the treatment groups. Adverse events were analyzed in the safety set.

6. Statistical analysis

For sample size calculation, the healing rate of artificial ulcers at 8 weeks was assumed to be 95.5% for tegoprazan and esomeprazole, with a non-inferiority margin of –10% and a power of 80% at a significant level of 2.5% (one-sided).15 While a direct comparison between vonoprazan and tegoprazan for artificial ulcer healing is lacking, an indirect comparison was conducted using data from reports. Specifically, it was found that vonoprazan exhibited comparable effectiveness to lansoprazole in healing gastric ulcers (93.5% for vonoprazan and 93.8% for lansoprazole), and similarly, tegoprazan demonstrated comparable efficacy to lansoprazole in gastric ulcer healing (95.0% for tegoprazan and 95.7% for lansoprazole).6,11 The total sample size was 160 subjects, with 80 patients per treatment group, considering a 15% drop-out.

For continuous variables, the values are provided as the number of subjects, mean, standard deviation, median, minimum and maximum. For categorical variables, the values are presented as frequencies and percentages. The non-inferiority test of tegoprazan versus esomeprazole in healing rate was to be declared if the lower bound of the two-sided 95% confidence interval for the difference between the two arms was greater than the non-inferiority margin, –10%. Continuous variables were compared by the Student t-test or Wilcoxon rank-sum test depending on whether the normality assumption was satisfied. Categorical variables were compared by the chi-square test or Fisher exact test depending on whether 20% or more of cells with an expected frequency of 5 or less were found.

All two-sided statistical tests were performed at a significance level of 5% unless otherwise specified. Statistical analyses were performed using SAS 9.4 (SAS Institution Inc., Cary, NC, USA).

RESULTS

1. Baseline characteristics

Among the 167 patients with an artificial ulcer after ESD who were screened, three were ineligible based on the inclusion/exclusion criteria, and four withdrew their consent. These participants were considered to have screening failure, and the remaining 160 patients were randomized in a 1:1 ratio to one of the two treatment arms: tegoprazan or esomeprazole. Among the 160 randomized patients, 16 (10.0%) were discontinued from the study due to the lack of viable data (n=10, 6.3%), violation of an inclusion/exclusion criteria (n=5, 3.1%), or withdrawal of consent before exposure to the study drug (n=1, 0.6%) (Fig. 2). The baseline characteristics of the patients are summarized in Table 1. No significant differences in baseline characteristics were observed between the treatment groups.

Figure 2. Disposition of patients included in this study.


Baseline Characteristic of Patients in the Full Analysis Set.


CharacteristicTegoprazan group (n=76)Esomeprazole group (n=68)
Sex, No. (%)
Male57 (75.0)46 (67.7)
Female19 (25.0)22 (32.3)
Age, mean±SD, yr62.0±7.463.0±7.8
Social history, No. (%)
Smoking16 (21.1)9 (13.2)
Alcohol29 (38.2)18 (26.5)
Pre-procedural histology, No. (%)
Adenoma, low grade dysplasia41 (54.0)37 (54.4)
Adenoma, high grade dysplasia13 (17.1)13 (19.1)
Differentiated adenocarcinoma17 (22.4)17 (25.0)
Undifferentiated adenocarcinoma2 (2.6)1 (1.5)
Mixed3 (4.0)0
Ulcer size immediately after ESD, mean±SD, mm2507.1±277.7562.9±324.8

ESD, endoscopic submucosal dissection..



2. Ulcer healing

The healing rates of artificial ulcers at 4 weeks were 30.3% (23/76) and 22.1% (15/68) in tegoprazan group and in esomeprazole group, respectively. The percentage difference between the tegoprazan group and esomeprazole group was <–10% (95% confidence interval, –6.07 to 22.48), which confirmed the non-inferiority of the tegoprazan group in comparison to the esomeprazole group. At 8 weeks after ESD, the cumulative healing rates of artificial ulcers were 73.7% (56/76) and 77.9% (53/68) in tegoprazan and esomeprazole groups, respectively (95% confidence interval, –18.23 to 9.71). The results are summarized in Table 2. Immediately after ESD, the ulcer size was 508.18±274.10 mm2 and 585.63±309.72 mm2 in tegoprazan group and esomeprazole groups, respectively (p=0.180). Four weeks after ESD, the ulcer size was 51.63±75.06 mm2 and 60.26±79.51 mm2 in tegoprazan and esomeprazole groups, respectively (p=0.400). Eight weeks after ESD, the ulcer size was 2.64±7.93 mm2 and 8.19±41.68 mm2 in tegoprazan and esomeprazole groups, respectively (p=0.761). The two groups showed no difference in changes in ulcer stages. A summary of the changes in ulcer stages can be found in Table 3.


Cumulative Healing Rates of Artificial Ulcers.


VariableHealing of the artificial ulcer (%)Difference, % (95% CI)p-value
4 wk8.20 (–6.07 to 22.48)0.006
Tegoprazan group30.3 (23/76)
Esomeprazole group22.1 (15/68)
8 wk–4.20 (–18.23 to 9.71)0.210
Tegoprazan group73.7 (56/76)
Esomeprazole group77.9 (53/68)

Data are presented as percentages with number of subjects in parentheses, confidence interval (CI), non-inferiority margin –10%..




Changes in Ulcer Stages at 4 and 8 Weeks after ESD.


Tegoprazan
group (n=74)
Esomeprazole
group (n=67)
4 wk after ESD
A1/A28 (10.8)10 (14.9)
H1/H243 (58.1)42 (62.7)
S1/S223 (31.1)15 (22.4)
8 wk after ESD
A1/A21 (1.4)2 (3.0)
H1/H217 (23.0)12 (17.9)
S1/S256 (75.7)53 (79.1)

Data are presented as number (%)..

ESD, endoscopic submucosal dissection..



At 4 weeks after ESD, the shrinkage rates of artificial ulcers were 85.6% in tegoprazan group and 85.0% in esomeprazole group, respectively (p=0.897). At 8 weeks after ESD, the shrinkage rates of artificial ulcers were 94.9% and 94.2% in the tegoprazan and esomeprazole groups, respectively (p=0.842).

3. Delayed bleeding and safety

Delayed bleeding occurred in two patients (2.6%) from the tegoprazan group and in one patient (1.5%) from the esomeprazole group (p=1.000). In all cases, melena was the first sign of delayed bleeding. One patient from the tegoprazan group experienced melena 9 days after ESD, and another patient from the same group had melena 14 days after ESD. One patient from the esomeprazole group had melena 10 days after ESD. Gastroscopy confirmed bleeding from the ESD site, with Forrest Ib observed in one patient from the esomeprazole group and Forrest IIa in two patients from the tegoprazan group. Delayed bleeding was successfully managed using endoscopic hemostasis in all the patients. Hemoglobin levels dropped from 2.1 g/dL to 3.2 g/dL.

Safety analysis was performed in 159 patients who received ≥1 dose of the study drug and underwent ≥1 safety assessment in this clinical trial. Among the 159 patients, 15 cases of TEAEs were reported in 12 patients. In the esomeprazole group only, one nausea, urticarial, and skin rash were reported as drug-related TEAEs (n=1, 1.28%).

4. Serum gastrin level

The baseline serum gastrin levels were 94.99±105.78 pg/mL and 100.81±119.89 pg/mL for the tegoprazan and esomeprazole groups, respectively (Fig. 3). The serum gastrin levels were 82.14±70.5 pg/mL and 86.52±72.57 pg/mL at 4 weeks and 99.22±86.24 pg/mL and 96.21±81.65 pg/mL at 8 weeks for the tegoprazan and esomeprazole groups, respectively. The changes in serum gastrin levels did not differ significantly between the tegoprazan and esomeprazole groups.

Figure 3. Changes in the serum gastrin level before and after tegoprazan and esomeprazole administration.

DISCUSSION

In this study, we found that 50 mg of tegoprazan was not inferior to 40 mg of esomeprazole in treating artificial ulcers after ESD for gastric neoplasia. The healing rate of artificial ulcers at 4 weeks after ESD was higher in the tegoprazan group than in the esomeprazole group, whereas cumulative healing rate at 8 weeks after ESD did not show a significant difference between the two groups. From these results, it is plausible that tegoprazan has a more potent acid-suppressive effect than esomeprazole; therefore, the healing process after ESD progressed rapidly in the tegoprazan group. Some studies have observed that vonoprazan, another P-CAB, was superior to PPIs in the healing of artificial ulcers after ESD for gastric neoplasia, indicating similarities with our study.9,16 However, it is still uncertain whether P-CAB is superior to PPI in the healing of artificial ulcers after ESD for gastric neoplasia. A systematic review and meta-analysis showed that vonoprazan was superior to PPI at 4 weeks after ESD,17 whereas another recent systematic review and meta-analysis showed that there was no difference between vonoprazan and PPI.18

The healing rate of artificial ulcers at 4 weeks after administration of P-CABs or PPIs was reported to range from less than 10% to over 90% in various studies.16,19,20 This large variation among the studies might result from interpretation of H3 stage ulcers according to the Sakita-Miwa classification.21 In this study, the healing rates of artificial ulcers were 30.3% in the tegoprazan group and 22.1% in the esomeprazole group at 4 weeks after ESD. This result was similar to a recent study comparing the efficacy of vonoprazan and lansoprazole treatment for artificial ulcers.19 We strictly interpreted the ulcer stages and even minute ulcer bases were classified as healing stages. Additionally, the shrinkage rates of artificial ulcers should not be misinterpreted as complete healing. At 8 weeks after ESD, the artificial ulcers healed by more than 70% in both groups in this study. Considering these results, acid-reducing agents should be administered at least 8 weeks after ESD. Since cumulative ulcer healing rates at 8 weeks after ESD were not 100% in both groups, an adequate duration of acid-reducing agents used after ESD for gastric neoplasia should be elucidated in further studies.

Our study did not show any difference in delayed bleeding rates between the tegoprazan and esomeprazole groups. Delayed bleeding was not the main outcome of our study, and the number of patients enrolled in this study might not have been sufficient. Considering that most delayed bleeding occurs within a week after ESD,22 delayed bleeding may be preventable with more potent acid suppression. A large-scale prospective study is needed to elucidate the effect of tegoprazan on delayed bleeding.

Although P-CABs can overcome some of the unmet needs of PPIs, they still have some limitations in clinical practice. It is well known that serum gastrin levels might increase after administration of P-CABs.23 Tegoprazan has a different chemical structure than vonoprazan and revaprazan. There were no changes in the serum gastrin levels in either group in this study. This was similar to the results of previous studies.11,24 Therefore, tegoprazan might be safely administered for up to 8 weeks. Further studies with large numbers of patients are warranted.

The strength of this study is that it is a multicenter, randomized, double-blind, active-controlled study. Despite this strength, this is a non-inferiority study, and it cannot be concluded that 50 mg of tegoprazan is superior to 40 mg of esomeprazole in the healing of artificial ulcers after ESD for gastric neoplasia. Another limitation is that intravenous pantoprazole was administered for 48 hours before starting oral tegoprazan or esomeprazole because tegoprazan cannot be administered intravenously. Therefore, the immediate effect of tegoprazan after ESD was not evaluated in this study. Hemoglobin levels were not checked within 2 weeks after ESD, which may lead to underestimation of delayed bleeding occurrences.

In conclusion, this is the first study to investigate the effect of tegoprazan on the healing of artificial ulcers after ESD for gastric neoplasia. Tegoprazan showed a similar effect on post-ESD artificial ulcer healing in comparison to esomeprazole, constituting that tegoprazan can be a new option for the treatment of ESD-induced artificial ulcers.

ACKNOWLEDGEMENTS

This study was supported by HK Inno.N Corp. HK Inno.N provided financial support and study drug.

CONFLICTS OF INTEREST

This study was supported by HK Inno.N Corp. HK Inno.N provided financial support and study drug. However, no role in the design of this study, study conduct, data analysis, and interpretation of the data.

B.W.K. and G.H.K. are editorial board members of the journal but were not involved in the peer reviewer selection, evaluation, or decision process of this article. No other potential conflicts of interest relevant to this article were reported.

AUTHOR CONTRIBUTIONS

Study concept and design: J.J.P. Data acquisition: B.W.K., J.J.P., H.S.M., W.S.L., K.N.S., G.H.B., Y.J.L., H.L.L., Y.H.Y., J.C.P., I.K.S., H.C., J.S.M., G.H.K., S.J.H., H.S.C. Data analysis and interpretation: B.W.K. Drafting of the manuscript: B.W.K. Critical revision of the manuscript for important intellectual content: J.J.P., H.S.M., W.S.L., K.N.S., G.H.B., Y.J.L., H.L.L., Y.H.Y., J.C.P., I.K.S., H.C., J.S.M., G.H.K., S.J.H., H.S.C. Statistical analysis: B.W.K. Obtained funding: J.J.P. Study supervision: J.J.P.

Fig 1.

Figure 1.A diagram indicating the progression of the study. IV, intravenous; ESD, endoscopic submucosal dissection.
Gut and Liver 2024; 18: 257-264https://doi.org/10.5009/gnl230242

Fig 2.

Figure 2.Disposition of patients included in this study.
Gut and Liver 2024; 18: 257-264https://doi.org/10.5009/gnl230242

Fig 3.

Figure 3.Changes in the serum gastrin level before and after tegoprazan and esomeprazole administration.
Gut and Liver 2024; 18: 257-264https://doi.org/10.5009/gnl230242

Baseline Characteristic of Patients in the Full Analysis Set


CharacteristicTegoprazan group (n=76)Esomeprazole group (n=68)
Sex, No. (%)
Male57 (75.0)46 (67.7)
Female19 (25.0)22 (32.3)
Age, mean±SD, yr62.0±7.463.0±7.8
Social history, No. (%)
Smoking16 (21.1)9 (13.2)
Alcohol29 (38.2)18 (26.5)
Pre-procedural histology, No. (%)
Adenoma, low grade dysplasia41 (54.0)37 (54.4)
Adenoma, high grade dysplasia13 (17.1)13 (19.1)
Differentiated adenocarcinoma17 (22.4)17 (25.0)
Undifferentiated adenocarcinoma2 (2.6)1 (1.5)
Mixed3 (4.0)0
Ulcer size immediately after ESD, mean±SD, mm2507.1±277.7562.9±324.8

ESD, endoscopic submucosal dissection.



Cumulative Healing Rates of Artificial Ulcers


VariableHealing of the artificial ulcer (%)Difference, % (95% CI)p-value
4 wk8.20 (–6.07 to 22.48)0.006
Tegoprazan group30.3 (23/76)
Esomeprazole group22.1 (15/68)
8 wk–4.20 (–18.23 to 9.71)0.210
Tegoprazan group73.7 (56/76)
Esomeprazole group77.9 (53/68)

Data are presented as percentages with number of subjects in parentheses, confidence interval (CI), non-inferiority margin –10%.



Changes in Ulcer Stages at 4 and 8 Weeks after ESD


Tegoprazan
group (n=74)
Esomeprazole
group (n=67)
4 wk after ESD
A1/A28 (10.8)10 (14.9)
H1/H243 (58.1)42 (62.7)
S1/S223 (31.1)15 (22.4)
8 wk after ESD
A1/A21 (1.4)2 (3.0)
H1/H217 (23.0)12 (17.9)
S1/S256 (75.7)53 (79.1)

Data are presented as number (%).

ESD, endoscopic submucosal dissection.


References

  1. Uedo N, Takeuchi Y, Yamada T, et al. Effect of a proton pump inhibitor or an H2-receptor antagonist on prevention of bleeding from ulcer after endoscopic submucosal dissection of early gastric cancer: a prospective randomized controlled trial. Am J Gastroenterol 2007;102:1610-1616.
    Pubmed CrossRef
  2. Ye BD, Cheon JH, Choi KD, et al. Omeprazole may be superior to famotidine in the management of iatrogenic ulcer after endoscopic mucosal resection: a prospective randomized controlled trial. Aliment Pharmacol Ther 2006;24:837-843.
    Pubmed CrossRef
  3. An JY, Kim BW, Kim JS, Park JM, Kim TH, Lee J. The use of endoscopic clipping in preventing delayed complications after endoscopic resection for superficial non-ampullary duodenal tumors. Clin Endosc 2021;54:563-569.
    Pubmed KoreaMed CrossRef
  4. Chey WD, Mody RR, Wu EQ, et al. Treatment patterns and symptom control in patients with GERD: US community-based survey. Curr Med Res Opin 2009;25:1869-1878.
    Pubmed CrossRef
  5. Jung YS, Kim EH, Park CH. Systematic review with meta-analysis: the efficacy of vonoprazan-based triple therapy on Helicobacter pylori eradication. Aliment Pharmacol Ther 2017;46:106-114.
    Pubmed CrossRef
  6. Miwa H, Uedo N, Watari J, et al. Randomised clinical trial: efficacy and safety of vonoprazan vs. lansoprazole in patients with gastric or duodenal ulcers: results from two phase 3, non-inferiority randomised controlled trials. Aliment Pharmacol Ther 2017;45:240-252.
    Pubmed KoreaMed CrossRef
  7. Oshima T, Arai E, Taki M, et al. Randomised clinical trial: vonoprazan versus lansoprazole for the initial relief of heartburn in patients with erosive oesophagitis. Aliment Pharmacol Ther 2019;49:140-146.
    Pubmed CrossRef
  8. Hamada K, Uedo N, Tonai Y, et al. Efficacy of vonoprazan in prevention of bleeding from endoscopic submucosal dissection-induced gastric ulcers: a prospective randomized phase II study. J Gastroenterol 2019;54:122-130.
    Pubmed CrossRef
  9. Tsuchiya I, Kato Y, Tanida E, et al. Effect of vonoprazan on the treatment of artificial gastric ulcers after endoscopic submucosal dissection: prospective randomized controlled trial. Dig Endosc 2017;29:576-583.
    Pubmed CrossRef
  10. Takahashi N, Take Y. Tegoprazan, a novel potassium-competitive acid blocker to control gastric acid secretion and motility. J Pharmacol Exp Ther 2018;364:275-286.
    Pubmed CrossRef
  11. Cho YK, Choi MG, Choi SC, et al. Randomised clinical trial: tegoprazan, a novel potassium-competitive acid blocker, or lansoprazole in the treatment of gastric ulcer. Aliment Pharmacol Ther 2020;52:789-797.
    Pubmed KoreaMed CrossRef
  12. Choi YJ, Lee YC, Kim JM, et al. Triple therapy-based on tegoprazan, a new potassium-competitive acid blocker, for first-line treatment of Helicobacter pylori infection: a randomized, double-blind, phase III, clinical trial. Gut Liver 2022;16:535-546.
    Pubmed KoreaMed CrossRef
  13. Lee KJ, Son BK, Kim GH, et al. Randomised phase 3 trial: tegoprazan, a novel potassium-competitive acid blocker, vs. esomeprazole in patients with erosive oesophagitis. Aliment Pharmacol Ther 2019;49:864-872.
    Pubmed KoreaMed CrossRef
  14. Kim SH, Cho KB, Chun HJ, et al. Randomised clinical trial: comparison of tegoprazan and placebo in non-erosive reflux disease. Aliment Pharmacol Ther 2021;54:402-411.
    Pubmed KoreaMed CrossRef
  15. Takahashi K, Sato Y, Kohisa J, et al. Vonoprazan 20 mg vs lansoprazole 30 mg for endoscopic submucosal dissection-induced gastric ulcers. World J Gastrointest Endosc 2016;8:716-722.
    Pubmed KoreaMed CrossRef
  16. Maruoka D, Arai M, Kasamatsu S, et al. Vonoprazan is superior to proton pump inhibitors in healing artificial ulcers of the stomach post-endoscopic submucosal dissection: a propensity score-matching analysis. Dig Endosc 2017;29:57-64.
    Pubmed CrossRef
  17. Kang H, Kim BJ, Choi G, Kim JG. Vonoprazan versus proton pump inhibitors for the management of gastric endoscopic submucosal dissection-induced artificial ulcer: a systematic review with meta-analysis. Medicine (Baltimore) 2019;98:e15860.
    Pubmed KoreaMed CrossRef
  18. Miao T, Zhang Y, Bai L, Yang X, Wen X. Vonoprazan vs. lansoprazole for the treatment of endoscopic submucosal dissection induced gastric ulcer: a systematic review and meta-analysis. Rev Esp Enferm Dig 2023;115:168-174.
    Pubmed CrossRef
  19. Kawai D, Takenaka R, Ishiguro M, et al. Vonoprazan versus lansoprazole in the treatment of artificial gastric ulcers after endoscopic submucossal dissection: a randomized, open-label trial. BMC Gastroenterol 2021;21:236.
    Pubmed KoreaMed CrossRef
  20. Ishii Y, Yamada H, Sato T, et al. Effects of vonoprazan compared with esomeprazole on the healing of artificial postendoscopic submucosal dissection ulcers: a prospective, multicenter, two-arm, randomized controlled trial. Gastroenterol Res Pract 2018;2018:1615092.
    Pubmed KoreaMed CrossRef
  21. Sakita T, Fukutomi H. Endoscopic diagnosis. In: Yoshitoshi Y, ed. All about gastric and duodenal ulcer. Tokyo: Nankodo, 1972:200-211.
  22. Choi IJ, Lee NR, Kim SG, et al. Short-term outcomes of endoscopic submucosal dissection in patients with early gastric cancer: a prospective multicenter cohort study. Gut Liver 2016;10:739-748.
    Pubmed KoreaMed CrossRef
  23. Jenkins H, Sakurai Y, Nishimura A, et al. Randomised clinical trial: safety, tolerability, pharmacokinetics and pharmacodynamics of repeated doses of TAK-438 (vonoprazan), a novel potassium-competitive acid blocker, in healthy male subjects. Aliment Pharmacol Ther 2015;41:636-648.
    Pubmed KoreaMed CrossRef
  24. He J, Cao G, Yu J, et al. Safety, tolerability and pharmacokinetics of single ascending and multiple oral doses of tegoprazan in healthy Chinese subjects. Clin Drug Investig 2021;41:89-97.
    Pubmed CrossRef
Gut and Liver

Vol.18 No.3
May, 2024

pISSN 1976-2283
eISSN 2005-1212

qrcode
qrcode

Share this article on :

  • line

Popular Keywords

Gut and LiverQR code Download
qr-code

Editorial Office