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Efficacy and Safety of Rebamipide Versus Its New Formulation, AD-203

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Efficacy and Safety of Rebamipide Versus Its New Formulation, AD-203 Gut and Liver https://doi.org/10.5009/gnl20338 pISSN 1976-2283 eISSN 2005-1212 Original Article Efficacy and Safety of Rebamipide versus Its New Formulation, AD-203, in Patients with Erosive Gastritis: A Randomized, Double- Blind, Active Control, Noninferiority, Multicenter, Phase 3 Study Gwang Ha Kim1, Hang Lak Lee2, Moon Kyung Joo3, Hong Jun Park4, Sung Woo Jung5, Ok-Jae Lee6, Hyungkil Kim7, Hoon Jai Chun8, Soo Teik Lee9, Ji Won Kim10, Han Ho Jeon11, Il-Kwun Chung12, Hyun-Soo Kim13, Dong Ho Lee14, Kyoung-Oh Kim15, Yun Jeong Lim16, Seun-Ja Park17, Soo-Jeong Cho18, Byung-Wook Kim19, Kwang Hyun Ko20, Seong Woo Jeon21, Jae Gyu Kim22, In-Kyung Sung23, Tae Nyeun Kim24, Jae Kyu Sung25, and Jong-Jae Park3 1Department of Internal Medicine, Pusan National University College of Medicine, and Biomedical Research Institute, Pusan National University Hospital, Busan, 2Department of Internal Medicine, Hanyang University Hospital, 3Division of Gastroenterology, Department of Internal Medicine, Korea University Guro Hospital, Seoul, 4Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, 5Division of Gastroenterology, Department of Internal Medicine, Korea University Ansan Hospital, Ansan, 6Department of Internal Medicine, Gyeongsang National University College of Medicine, Jinju, 7Department of Internal Medicine, Inha University School of Medicine, Incheon, 8Division of Gastroenterology and Hepatology, Department of Internal Medicine, Institute of Gastrointestinal Medical Instrument Research, Korea University College of Medicine, Seoul, 9Department of Internal Medicine, Jeonbuk National University Hospital, Jeonju, 10Department of Internal Medicine, SMG-SNU Boramae Medical Center, Seoul National University of College of Medicine, Seoul, 11Department of Internal Medicine, National Health Insurance Service Ilsan Hospital, Goyang, 12Department of Internal Medicine, Soonchunhyang University College of Medicine, Cheonan, 13Department of Internal Medicine, Chonnam National University Hospital, Gwangju, 14Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, 15Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, 16Department of Internal Medicine, Dongguk University College of Medicine, Seoul, 17Department of Internal Medicine, Kosin University Gospel Hospital, Kosin University College of Medicine, Busan, 18Department of Internal Medicine, Seoul National University College of Medicine, 19Department of Internal Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, 20Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, 21Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, 22Department of Internal Medicine, Chung-Ang University College of Medicine, 23Department of Internal Medicine, Konkuk University School of Medicine, Seoul, 24Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, and 25Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon, Korea Article Info Background/Aims: The mucoprotective drug rebamipide is used to treat gastritis and peptic Ⓡ Received November 12, 2020 ulcers. We compared the efficacy of Mucosta (rebamipide 100 mg) and its new formulation, AD- Revised December 10, 2020 203 (rebamipide 150 mg), in treating erosive gastritis. December 28, 2020 Accepted Methods: This double-blind, active control, noninferiority, multicenter, phase 3 clinical trial randomly assigned 475 patients with endoscopically proven erosive gastritis to two groups: AD-203 twice Corresponding Author daily or MucostaⓇ thrice daily for 2 weeks. The intention-to-treat (ITT) analysis included 454 patients Jong-Jae Park (AD-203, n=229; MucostaⓇ, n=225), and the per-protocol (PP) analysis included 439 patients (AD- ORCID https://orcid.org/0000-0002-4642-5405 203, n=224; MucostaⓇ, n=215). The posttreatment assessments included the primary (erosion im- E-mail [email protected] provement rate) and secondary endpoints (erosion and edema cure rates; improvement rates of red- ness, hemorrhage, and gastrointestinal symptoms). Drug-related adverse events were evaluated. Results: According to the ITT analysis, the erosion improvement rates (posttreatment) in AD- 203-treated and MucostaⓇ-treated patients were 39.7% and 43.8%, respectively. According to the PP analysis, the erosion improvement rates (posttreatment) in AD-203-treated and MucostaⓇ- treated patients were 39.3% and 43.7%, respectively. The one-sided 97.5% lower limit for the improvement rate difference between the study groups was −4.01% (95% confidence interval [CI], –13.09% to 5.06%) in the ITT analysis and −4.44% (95% CI, –13.65% to 4.78%) in the PP analysis. The groups did not significantly differ in the secondary endpoints in either analysis. Twenty-four AD-203-treated and 20 MucostaⓇ-treated patients reported adverse events but no serious adverse drug reactions; both groups presented similar adverse event rates. Conclusions: The new formulation of rebamipide 150 mg (AD-203) twice daily was not inferior to rebamipide 100 mg (MucostaⓇ) thrice daily. Both formulations showed a similar efficacy in treat- ing erosive gastritis. (Gut Liver, Published online April 7, 2021) Key Words: Adverse drug reaction; Gastritis; Intention-to-treat analysis; Phase III clinical trial; Rebamipide Copyright © Gut and Liver. 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. www.gutnliver.org Gut and Liver, Published online April 7, 2021 INTRODUCTION of rebamipide, which diminishes its optimal therapeutic efficacy, has become a general concern. Gastritis is one of the most common diseases in Korean Recent efforts to improve patient adherence for drug in- adults. Generally, its diagnosis is based on endoscopic find- take have resulted in the release of incrementally modified ings, such as erosion, edema, redness, and hemorrhage. drug formulations. If a drug requiring thrice-daily admin- Especially, erosion as a distinct mucosal defect is observed istration is modified to a drug that is taken once or twice during acute exacerbation of acute gastritis and chronic a day, it can improve the therapeutic effect by increasing gastritis.1 The incidence of gastritis in Korea is higher patients’ compliance via a reduced dosing frequency. Re- than that of other digestive diseases, and the prevalence of cently, AD-203 (rebamipide 150 mg; Addpharma Co., Ltd., gastritis has been gradually increasing;2 thus, there is an Yongin, Korea), a new matrix-type sustained-release for- increasing demand for effective gastritis therapies. mulation of rebamipide using a low-viscosity water-soluble Gastritis treatment mainly involves the control of symp- polymer, was developed to decrease dosing frequency toms and improvement in gastric lesions, which can be from rebamipide 100 mg thrice a day to rebamipide 150 achieved with drugs that suppress gastric acid secretion, mg twice a day. However, whether a twice-daily dose of modulate gastrointestinal (GI) motility, and protect the AD-203 improves lesions in patients with gastritis remains gastric mucosa. Acid suppressing agents, such as proton unclear. Therefore, we conducted a randomized, double- pump inhibitors (PPIs) and H2-receptor antagonists, are blind, active control, non-inferiority, multicenter, phase commonly used with an excellent therapeutic effect in 3 clinical study to compare AD-203 (twice per day) with clinical practice. Especially, PPIs are effective and relatively rebamipide (thrice per day) based on safety, as well as im- safe drugs. However, they have following limitations; a provements in endoscopic findings and GI symptoms, in slow onset of action due to the mechanical limitation of patients with gastritis. prodrugs, a diminished inhibitory effect on gastric acid se- cretion when administered after a meal, and the difficulty in controlling nocturnal acid breakthrough.3 In addition, MATERIALS AND METHODS PPIs have several adverse effects in the stomach, such as oxyntic cell and enterochromaffin-like cell hyperplasia and 1. Study population the occurrence of hyperplastic and fundic gland polyps This study was a randomized, double-blind, active con- due to hypergastrinemia.4-6 Furthermore, some studies trol, non-inferiority, multicenter, phase 3 clinical trial con- have suggested that long-term PPI use might affect the ducted in Korea from September 2019 to February 2020. progression of atrophic gastritis and the development of Patients with gastritis were recruited from the following 25 gastric cancer.7,8 medical centers: Korea University Guro Hospital (Seoul), To overcome these limitations, gastric mucoprotective Gachon University Gil Medical Center (Incheon), Konkuk agents are frequently used alone or in combination with University Medical Center (Seoul), Gyeongsang National acid-suppressing agents. Owing to the well-documented University Hospital (Jinju), Korea University Ansan Hos- protective effect of rebamipide on the GI tract, the drug is pital (Ansan), Korea University Anam Hospital (Seoul), one of the most commonly used mucoprotective agents for Kosin University Gospel Hospital (Busan), National Health acute and
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