Phase III, randomised, double-blind, multicentre study to evaluate the efficacy and safety of vonoprazan compared with lansoprazole in Asian patients with erosive oesophagitis

Yinglian Xiao, Shutian Zhang, Ning Dai, Guijun Fei, Khean-Lee Goh, Hoon Jai Chun, Bor-Shyang Sheu, Chui Fung Chong, Nobuo Funao, Wen Zhou, Minhu Chen, Yinglian Xiao, Shutian Zhang, Ning Dai, Guijun Fei, Khean-Lee Goh, Hoon Jai Chun, Bor-Shyang Sheu, Chui Fung Chong, Nobuo Funao, Wen Zhou, Minhu Chen

Abstract

Objective: To establish the non-inferior efficacy of vonoprazan versus lansoprazole in the treatment of Asian patients with erosive oesophagitis (EO).

Design: In this phase III, double-blind, multicentre study, patients with endoscopically confirmed EO were randomised 1:1 to receive vonoprazan 20 mg or lansoprazole 30 mg, once daily for up to 8 weeks. The primary endpoint was EO healing rate at 8 weeks. The secondary endpoints were EO healing rates at 2 and 4 weeks. Safety endpoints included treatment-emergent adverse events (TEAEs).

Results: In the vonoprazan (n=238) and lansoprazole (n=230) arms, 8-week EO healing rates were 92.4% and 91.3%, respectively (difference 1.1% (95% CI -3.822% to 6.087%)). The respective 2-week EO healing rates were 75.0% and 67.8% (difference 7.2% (95% CI -1.054% to 15.371%)), and the respective 4-week EO healing rates were 85.3% and 83.5% (difference 1.8% (95% CI -4.763% to 8.395%)). In patients with baseline Los Angeles classification grade C/D, 2-week, 4-week and 8-week EO healing rates were higher with vonoprazan versus lansoprazole (2 weeks: 62.2% vs 51.5%, difference 10.6% (95% CI -5.708% to 27.002%); 4 weeks: 73.3% vs 67.2%, difference 6.2% (95% CI -8.884 to 21.223); and 8 weeks: 84.0% vs 80.6%, difference 3.4% (95% CI -9.187% to 15.993%)). Overall, EO healing rates appeared higher with vonoprazan versus lansoprazole. TEAE rates were 38.1% and 36.6% in the vonoprazan and lansoprazole group, respectively.

Conclusion: Our findings demonstrate the non-inferior efficacy of vonoprazan versus lansoprazole in terms of EO healing rate at 8 weeks in this population. Safety outcomes were similar in the two treatment arms.

Trial registration number: NCT02388724.

Keywords: erosive oesophagitis; gastric acid; gastro-oesophageal reflux disease; proton pump inhibition.

Conflict of interest statement

Competing interests: MC received speaker honorarium from Xian Janssen, AstraZeneca China, Ipsen Tianjin, Takeda China and CMS China. CFC is an employee of Takeda Development Center Asia, and stock shareholder in Air Liquide and Abbott Laboratories. NF is an employee of Takeda Pharmaceutical Company, and WZ is a former employee of Takeda Pharmaceutical Company. K-L G received fees for participating in an advisory committee or review panel and speaking and chairing for Takeda Pharmaceutical Company. All other authors declare no competing interests.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
Patient disposition. AE, adverse event; PTE, pretreatment event.
Figure 2
Figure 2
Rate of endoscopic healing of EO during the 2-week, 4-week and 8-week treatment period for the full analysis set (A) and patients with LA classification grade C/D (B). *Treatment difference between arms (95% CI). EO, erosive oesophagitis; LA, Los Angeles.

References

    1. Vakil N, van Zanten SV, Kahrilas P, et al. . The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am J Gastroenterol 2006;101:1900–20. quiz 1943 10.1111/j.1572-0241.2006.00630.x
    1. Eusebi LH, Ratnakumaran R, Yuan Y, et al. . Global prevalence of, and risk factors for, gastro-oesophageal reflux symptoms: a meta-analysis. Gut 2018;67:430–40. 10.1136/gutjnl-2016-313589
    1. Maradey-Romero C, Fass R. New and future drug development for gastroesophageal reflux disease. J Neurogastroenterol Motil 2014;20:6–16. 10.5056/jnm.2014.20.1.6
    1. Lundell LR, Dent J, Bennett JR, et al. . Endoscopic assessment of oesophagitis: clinical and functional correlates and further validation of the Los Angeles classification. Gut 1999;45:172–80. 10.1136/gut.45.2.172
    1. Ashida K, Sakurai Y, Hori T, et al. . Randomised clinical trial: vonoprazan, a novel potassium-competitive acid blocker, vs. lansoprazole for the healing of erosive oesophagitis. Aliment Pharmacol Ther 2016;43:240–51. 10.1111/apt.13461
    1. Freedberg DE, Kim LS, Yang Y-X. The risks and benefits of long-term use of proton pump inhibitors: expert review and best practice advice from the American gastroenterological association. Gastroenterology 2017;152:706–15. 10.1053/j.gastro.2017.01.031
    1. Fuchs KH, Babic B, Breithaupt W, et al. . EAES recommendations for the management of gastroesophageal reflux disease. Surg Endosc 2014;28:1753–73. 10.1007/s00464-014-3431-z
    1. Iwakiri K, Kinoshita Y, Habu Y, et al. . Evidence-Based clinical practice guidelines for gastroesophageal reflux disease 2015. J Gastroenterol 2016;51:751–67. 10.1007/s00535-016-1227-8
    1. Katz PO, Gerson LB, Vela MF. Guidelines for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol 2013;108:308–28. quiz 29 10.1038/ajg.2012.444
    1. Strand DS, Kim D, Peura DA. 25 years of proton pump inhibitors: a comprehensive review. Gut Liver 2017;11:27–37. 10.5009/gnl15502
    1. Tytgat GN. Shortcomings of the first-generation proton pump inhibitors. Eur J Gastroenterol Hepatol 2001;13 Suppl 1:S29–33.
    1. Hori Y, Imanishi A, Matsukawa J, et al. . 1-[5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monofumarate (TAK-438), a novel and potent potassium-competitive acid blocker for the treatment of acid-related diseases. J Pharmacol Exp Ther 2010;335:231–8. 10.1124/jpet.110.170274
    1. Hori Y, Matsukawa J, Takeuchi T, et al. . A study comparing the antisecretory effect of TAK-438, a novel potassium-competitive acid blocker, with lansoprazole in animals. J Pharmacol Exp Ther 2011;337:797–804. 10.1124/jpet.111.179556
    1. Matsukawa J, Hori Y, Nishida H, et al. . A comparative study on the modes of action of TAK-438, a novel potassium-competitive acid blocker, and lansoprazole in primary cultured rabbit gastric glands. Biochem Pharmacol 2011;81:1145–51. 10.1016/j.bcp.2011.02.009
    1. Shin JM, Inatomi N, Munson K, et al. . Characterization of a novel potassium-competitive acid blocker of the gastric H, K-ATPase, 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monofumarate (TAK-438). J Pharmacol Exp Ther 2011;339:412–20. 10.1124/jpet.111.185314
    1. Otake K, Sakurai Y, Nishida H, et al. . Characteristics of the novel potassium-competitive acid blocker vonoprazan fumarate (TAK-438). Adv Ther 2016;33:1140–57. 10.1007/s12325-016-0345-2
    1. Inatomi N, Matsukawa J, Sakurai Y, et al. . Potassium-Competitive acid blockers: advanced therapeutic option for acid-related diseases. Pharmacol Ther 2016;168:12–22. 10.1016/j.pharmthera.2016.08.001
    1. Piche T, Galmiche JP. Pharmacological targets in gastro-oesophageal reflux disease. Basic Clin Pharmacol Toxicol 2005;97:333–41. 10.1111/j.1742-7843.2005.pto_273.x
    1. Sachs G, Shin JM, Howden CW. Review article: the clinical pharmacology of proton pump inhibitors. Aliment Pharmacol Ther 2006;23 Suppl 2:2–8. 10.1111/j.1365-2036.2006.02943.x
    1. Andersson K, Carlsson E. Potassium-Competitive acid blockade: a new therapeutic strategy in acid-related diseases. Pharmacol Ther 2005;108:294–307. 10.1016/j.pharmthera.2005.05.005
    1. Ashida K, Sakurai Y, Nishimura A, et al. . Randomised clinical trial: a dose-ranging study of vonoprazan, a novel potassium-competitive acid blocker, vs. lansoprazole for the treatment of erosive oesophagitis. Aliment Pharmacol Ther 2015;42:685–95. 10.1111/apt.13331
    1. Takeda Pharmaceutical Company Ltd Takecab® (Vonoprazan fumarate), package insert [Japanese] 2018.
    1. Takeda Pharmaceutical Company Ltd Investigation of the efficacy and safety of TAK-390MR for erosive esophagitis. public disclosure synopsis 2010.
    1. Zheng R-N. Comparative study of omeprazole, lansoprazole, pantoprazole and esomeprazole for symptom relief in patients with reflux esophagitis. World J Gastroenterol 2009;15:990–5. 10.3748/wjg.15.990
    1. Sakurai Y, Nishimura A, Kennedy G, et al. . Safety, tolerability, pharmacokinetics, and pharmacodynamics of single rising TAK-438 (vonoprazan) doses in healthy male Japanese/non-Japanese subjects. Clin Transl Gastroenterol 2015;6:e94 10.1038/ctg.2015.18
    1. Kim K-M, Cho YK, Bae SJ, et al. . Prevalence of gastroesophageal reflux disease in Korea and associated health-care utilization: a national population-based study. J Gastroenterol Hepatol 2012;27:741–5. 10.1111/j.1440-1746.2011.06921.x
    1. Tan VP-Y, Wong BC, Wong WM, et al. . Gastroesophageal reflux disease: cross-sectional study demonstrating rising prevalence in a Chinese population. J Clin Gastroenterol 2016;50:e1–7. 10.1097/MCG.0000000000000304
    1. Dickman R, Maradey-Romero C, Gingold-Belfer R, et al. . Unmet needs in the treatment of gastroesophageal reflux disease. J Neurogastroenterol Motil 2015;21:309–19. 10.5056/jnm15105
    1. Higuchi K, Joh T, Nakada K, et al. . Is proton pump inhibitor therapy for reflux esophagitis sufficient?: a large real-world survey of Japanese patients. Intern Med 2013;52:1447–54. 10.2169/internalmedicine.52.0349
    1. Yuan Y, Hunt RH. W1100 intragastric pH holding time of pH. Gastroenterology 2010;138:S651 10.1016/S0016-5085(10)62998-8
    1. 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;41:636–48. 10.1111/apt.13121
    1. Hunt RH, Scarpignato C. Potassium-Competitive acid blockers (P-CABs): are they finally ready for prime time in acid-related disease? Clin Transl Gastroenterol 2015;6:e119 10.1038/ctg.2015.39
    1. Iwakiri K, Umegaki E, Hiramatsu N, et al. . Tu1059 a phase 3, randomized, double-blind, multicenter study to evaluate the efficacy and safety of TAK-438 (20 Mg once-daily) compared to lansoprazole (30 Mg once-daily) in patients with erosive esophagitis. Gastroenterology 2014;146:S-741 10.1016/S0016-5085(14)62682-2
    1. Takeda Pharmaceutical Company Ltd Takepron®Lansoprazole enteric-coated capsules. package insert 2017.
    1. Takeda Pharmaceutical Company Ltd Takepron® lansoprazole delayed-release capsules j.p., product information 2018.
    1. Brummer RJ, Geerling BJ, Stockbrügger RW. Initial and chronic gastric acid inhibition by lansoprazole and omeprazole in relation to meal administration. Dig Dis Sci 1997;42:2132–7. 10.1023/A:1018891106425
    1. Moules I, Garrett A, Brocklebank D, et al. . Gastric acid inhibition by the proton pump inhibitor lansoprazole is unaffected by food. Br J Clin Res 1993;4:153–61.
    1. Oshima T, Miwa H. Potent potassium-competitive acid blockers: a new era for the treatment of acid-related diseases. J Neurogastroenterol Motil 2018;24:334–44. 10.5056/jnm18029
    1. Kagami T, Sahara S, Ichikawa H, et al. . Potent acid inhibition by vonoprazan in comparison with esomeprazole, with reference to CYP2C19 genotype. Aliment Pharmacol Ther 2016;43:1048–59. 10.1111/apt.13588
    1. Mizokami Y, Oda K, Funao N, et al. . Vonoprazan prevents ulcer recurrence during long-term NSAID therapy: randomised, lansoprazole-controlled non-inferiority and single-blind extension study. Gut 2018;67:1042–51. 10.1136/gutjnl-2017-314010
    1. Astruc B, Jenkins H, Jenkins R. Effect of therapeutic and supratherapeutic doses of Vonoprazan on the QT/QTc interval in a phase I randomized study in healthy subjects. Clin Transl Sci 2017;10:208–16. 10.1111/cts.12452
    1. Jenkins H, Jenkins R, Patat A. Effect of multiple oral doses of the potent CYP3A4 inhibitor clarithromycin on the pharmacokinetics of a single oral dose of vonoprazan: a phase I, open-label, sequential design study. Clin Drug Investig 2017;37:311–6. 10.1007/s40261-016-0488-6

Source: PubMed

Sponsorit ja yhteistyökumppanit

Sairaudet

Huumeiden interventiot

3
Tilaa