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Mucosal Healing Effectiveness and Safety of Anaprazole, a Novel PPI, Vs CLINICAL TRIAL published: 14 July 2021 doi: 10.3389/fmed.2021.690995 Mucosal Healing Effectiveness and Safety of Anaprazole, a Novel PPI, vs. Rabeprazole in Patients With Duodenal Ulcers: A Randomized Double-Blinded Multicenter Phase II Clinical Trial Xu Shu 1†, Zhenhua Zhu 1†, Yu Fu 2†, Zhenyu Zhang 3, Jiangbin Wang 4, Xing Li 5, Edited by: Shuixiang He 6, Huizhen Fan 7, Side Liu 8, Guoxin Zhang 9, Jianhua Tang 10, Caibin Huang 11, Giuseppe Losurdo, Qin Du 12, Xiaoyan Wang 13, Baohong Xu 14, Yiqi Du 15, Qikui Chen 16, Bangmao Wang 17, University of Bari Medical School, Italy Ying Chen 18, Xianghui Duan 19, Yong Xie 1, Lijuan Huo 20*, Xiaohua Hou 2* and Nonghua Lu 1* Reviewed by: 1 Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, China, 2 Department of Edoardo Savarino, Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China, University Hospital of Padua, Italy 3 Department of Gastroenterology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China, 4 Department of Enzo Ieardi, Gastroenterology, China–Japan Union Hospital of Jilin University, Changchun, China, 5 Department of Gastroenterology, University of Bari Aldo Moro, Italy Jiangxi Pingxiang People’s Hospital, Pingxiang, China, 6 Department of Gastroenterology, First Affiliated Hospital of Xi’an *Correspondence: Jiaotong University, Xi’an, China, 7 Department of Gastroenterology, Yichun People’s Hospital, Yichun, China, 8 Department of Nonghua Lu Gastroenterology, Nanfang Hospital, Nanfang Medical University, Guangzhou, China, 9 Department of Gastroenterology, [email protected] Jiangsu Province Hospital, Nanjing, China, 10 Department of Gastroenterology, Ganzhou People’s Hospital, Ganzhou, China, Xiaohua Hou 11 Department of Gastroenterology, First Affiliated Hospital of Gannan Medical University, Ganzhou, China, 12 Department of [email protected] Gastroenterology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China, 13 Department Lijuan Huo of Gastroenterology, The Third Hospital of Central South University, Changsha, China, 14 Department of Gastroenterology, [email protected] Beijing Luhe Hospital, Capital Medical University, Beijing, China, 15 Department of Gastroenterology, Changhai Hospital, Shanghai, China, 16 Department of Gastroenterology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, †These authors have contributed China, 17 Department of Gastroenterology, Tianjin Medical University General Hospital, Tianjin, China, 18 Clinical Development, equally to this work Xuanzhu Biopharmaceutical Co., Ltd., Beijing, China, 19 Statistics, Xuanzhu Biopharmaceutical Co., Ltd., Beijing, China, 20 Department of Gastroenterology, The First Hospital of Shanxi Medical University, Taiyuan, China Specialty section: This article was submitted to Gastroenterology, Background: Proton pump inhibitors (PPIs) are validated gastric acid suppressors and a section of the journal have been widely used to treat patients with active duodenal ulcers. Although existing Frontiers in Medicine PPIs have shown great efficacy, many scientists are still devoted to developing more Received: 05 April 2021 Accepted: 08 June 2021 effective PPIs with better safety profile. Herein, we aimed to compare the safety and Published: 14 July 2021 efficacy of anaprazole in duodenal mucosal healing, a novel PPI, to that of rabeprazole. Citation: Methods: In this multicenter, randomized, positive-controlled, double-blinded, Shu X, Zhu Z, Fu Y, Zhang Z, Wang J, Li X, He S, Fan H, Liu S, Zhang G, parallel-group phase II clinical trial, a total of 150 qualified patients with endoscopically Tang J, Huang C, Du Q, Wang X, confirmed active duodenal ulcers were randomized (1:1:1) to receive rabeprazole 10 mg, Xu B, Du Y, Chen Q, Wang B, Chen Y, Duan X, Xie Y, Huo L, Hou X and Lu N anaprazole 20 mg or anaprazole 40 mg for 4 weeks. The ulcer healing rates after 4 (2021) Mucosal Healing Effectiveness weeks of treatment were compared between groups by independent central review and and Safety of Anaprazole, a Novel PPI, investigator review. In addition, symptoms and safety were evaluated. vs. Rabeprazole in Patients With Duodenal Ulcers: A Randomized Results: Based on the independent central review, the ulcer healing rates of the 10 mg Double-Blinded Multicenter Phase II Clinical Trial. Front. Med. 8:690995. rabeprazole, 20 mg anaprazole and 40 mg anaprazole groups were 88.0, 85.1, and doi: 10.3389/fmed.2021.690995 87.5%, respectively, in the FAS population and 88.9, 86.0, and 90.9%, respectively, Frontiers in Medicine | www.frontiersin.org 1 July 2021 | Volume 8 | Article 690995 Shu et al. Efficacy and Safety of Anaprazole, a Novel PPI in the PPS population. The ulcer healing rate difference between anaprazole 20 mg and Rabeprazole 10 mg is −2.9% (95% CI, −16.5–10.7%), and −0.5% (95% CI, −13.5–12.5%) between anaprazole 40 mg and Rabeprazole 10 mg, in the FAS population. Based on the investigator review, the ulcer healing rates of the 10 mg rabeprazole, 20 mg anaprazole, and 40 mg anaprazole groups were 72.0, 70.2, and 77.1%, respectively, in the FAS population and 75.6, 72.1, and 79.5%, respectively, in the PPS population. The ulcer healing rate difference between anaprazole 20 mg and Rabeprazole 10 mg is −1.8% (95% CI, −19.8–16.3%), and 5.1% (95% CI, −12.2–22.3%) between anaprazole 40 mg and Rabeprazole 10 mg, in the FAS population. Most patients (>90%) eventually achieved complete symptom relief. The incidence rates of adverse events were of no significant differences among the treatment groups. Potential possible better liver tolerance was observed in two anaprazole dose groups than rabeprazole 10 mg group. Conclusion: Both at a dosage of 20 and 40 mg daily, anaprazole, is effective with good safety profile in the treatment of active duodenal ulcers in this Phase 2 study, which allows anaprazole to be advanced to a phase III clinical trial. Clinical Trial Registration: https://www.clinicaltrials.gov/ct2/results?cond=&term= NCT04503629&cntry=&state=&city=&dist=, Identifier: CTR20181464, NCT04503629. Keywords: proton pump inhibitors, duodenal ulcer, anaprazole, rabeprazole, peptic ulcer WHAT IS KNOWN Previous preclinical trials showed that rabeprazole, a commonly used PPI in DU patients that has shown great Duodenal ulcer (DU) is a common acid-related curative efficacy in terms of promoting ulcer healing and clinical gastrointestinal disorder. symptom relief, is superior to other PPIs, such as omeprazole, Proton pump inhibitors (PPIs) are validated gastric acid lansoprazole and pantoprazole, in the inhibition of H+/K+- suppressors. PPIs have been widely used to treat patients with ATPase (2–4). Although 7-day dose-ranging studies have verified active duodenal ulcers. that rabeprazole 20 mg daily is more likely to provide an optimal Anaprazole {(R)-2-[[[4-(3-methoxylpropoxy)-3-methyl-2- gastric acid inhibitory effect, particularly in patients with peptic pyridyl]methyl]sulfiny]-6,7-dihydro-3H-benzofuro [5,6-d] ulcer (5, 6), 10mg rabeprazole per day is still the most extensively imidazole sodium}, a newly developed PPI with new used dosage in China for individuals with peptic ulcer diseases. chemical structure. Although existing PPIs have shown great efficacy, there are clinical needs for PPIs with better safety profile in case of WHAT IS NEW HERE various adverse reaction of PPIs. Many scientists are devoted to developing more effective PPIs with better safety profile. Anaprazole, a novel PPI, can be used to treat patients with active Anaprazole is developed from these needs. duodenal ulcers effectively. Anaprazole {(R)-2-[[[4-(3-methoxylpropoxy)-3-methyl- Both at a dosage of 20 and 40 mg daily, anaprazole, are 2-pyridyl]methyl]sulfiny]-6,7-dihydro-3H-benzofuro [5,6-d] effective and have good safety profile in the treatment of active imidazole sodium}, a newly developed PPI with new chemical duodenal ulcers. structure. In preclinical and phase I clinical trials, anaprazole Potential possible better liver tolerance was observed in two has shown an equivalent half-life and pharmacodynamics to anaprazole dose groups than rabeprazole 10 mg group. that of rabeprazole in the suppression of gastric acid secretion but has demonstrated better safety profiles with lower incidence INTRODUCTION rate of gastrointestinal adverse reaction (7). A randomized, double-blinded, placebo parallel controlled phase 1 study of Duodenal ulcer (DU) is a common acid-related gastrointestinal multiple ascending dose administration of anaprazole in healthy disorder that has a high incidence in clinical practice in Chinese subjects has investigated pharmacodynamics data (the China. Consequently, gastric acid suppression has been widely time percentage of gastric pH value > 3 and pH value > 4in24h accepted as the main treatment strategy for DUs worldwide. gastric pH monitoring post dose at day 6). Anaprazole 20 mg Comparative studies have demonstrated that proton pump (20mg, qd, 6 days) shows 61.16% (pH > 3) and 49.61% (pH > inhibitors (PPIs) can provide better improvement of acid 4). Anaprazole 40mg (40mg, qd, 6 days) shows 71.29% (pH > 3) suppression, ulcer healing and pain relief than histamine 2 and 62.24% (pH > 4). In addition, anaprazole has less influence receptor antagonists (H2RAs) (1). of CYP2C19 genotypes. Anaprazole is metabolized via systemic Frontiers in Medicine | www.frontiersin.org 2 July 2021 | Volume 8 | Article 690995 Shu et al. Efficacy and Safety of Anaprazole, a Novel PPI non-enzymatic
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