Vonoprazan prevents ulcer recurrence during long-term NSAID therapy: randomised, lansoprazole-controlled non-inferiority and single-blind extension study

Abstract

Objective: To assess the non-inferiority of vonoprazan to lansoprazole for secondary prevention of non-steroidal anti-inflammatory drug (NSAID)-induced peptic ulcer (PU) and the safety of vonoprazan during extended use.

Design: A phase 3, 24-week, multicenter, randomised, double-blind (DB), active-controlled study, followed by a phase 3, ≥28 week, multicenter, single-blind, parallel-group extension study (EXT) in outpatients (n=642) receiving long-term NSAID therapy who are at risk of PU recurrence. The patients received vonoprazan (10 mg or 20 mg) or lansoprazole 15 mg once daily. For DB, non-inferiority of the proportion of patients with recurrent PU within 24 weeks was analysed by Farrington and Manning test (significance level 2.5%, non-inferiority margin 8.3%; primary endpoint), recurrent PU within 12 weeks, bleeding and time-to-event of PU (secondary endpoint) and treatment-emergent adverse events (TEAEs). For EXT, TEAEs (primary endpoint), recurrent PU and safety (secondary) were assessed up to 104 weeks for patients in the extension study.

Results: The non-inferiority of vonoprazan 10 mg and 20 mg to lansoprazole 15 mg was verified (percentage difference -2.2%,95% CI -6.2% to 1.8%, p<0.001; -2.1%,95% CI -6.1% to 2.0%, p<0.001, respectively). The proportion of patients with endoscopically confirmed recurrent PU within 24 weeks was 3.3%, 3.4% and 5.5%, for vonoprazan 10 mg, 20 mg and lansoprazole 15 mg, respectively. No significant safety concerns were identified.

Conclusion: The non-inferiority of vonoprazan (10 and 20 mg) was verified in patients receiving long-term NSAIDs in DB; it was effective and well tolerated in EXT for longer than 1 year, with a safety profile similar to lansoprazole (15 mg).

Trial registration numbers: NCT01452750, NCT01456260; Results.

Keywords: NSAIDs; lansoprazole osteoarthritis; non-inferiority; peptic ulcer; potassium-competitive acid blockers; rheumatoid arthritis; vonoprazan.

Conflict of interest statement

Competing interests: YM has served as a consultant for, received grant and honorarium from Takeda Pharmaceutical Company. KO, NF and AN are employees of Takeda Pharmaceutical Company. SS has served as a consultant for and received a grant, honorarium and travel fee from Takeda Pharmaceutical Company. TK, KA and KS have served as a consultant and received a grant and honorarium from Takeda Pharmaceutical Company.

© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Figures

Figure 1

Patient disposition in the double-blind (A) and extension (B) studies.(A) Phase 3, multicenter, randomised, double-blind, parallel-group, non-inferiority study conducted to evaluate the non-inferiority of vonoprazan to lansoprazole in preventing occurrence of secondary ulcers in patients with a history of endoscopically confirmed gastric or duodenal ulcer (peptic ulcer) who require long-term NSAID therapy. (B) Phase 3, multicenter, single-blind, parallel-group extension study to evaluate the safety and ulcer recurrence during long-term drug exposure; subjects who completed the non-inferiority study were eligible for enrolment. One patient did not receive study medication. One patient was excluded due to protocol violations.

Figure 2

Peptic ulcer recurrence at week 24. The proportion of patients in the full analysis set population with endoscopically confirmed recurrent peptic ulcers within 24 weeks was lower for the vonoprazan 10 mg and 20 mg groups compared with the lansoprazole 15 mg group. *Non-inferiority p

Figure 3

Kaplan-Meier cumulative incidence of peptic ulcer recurrence (A) and bleeding (B)The cumulative incidence rates of peptic ulcer recurrence and bleeding occurrence were similar or lower in both vonoprazan groups compared with the lansoprazole group.

Figure 4

Mean serum gastrin concentrations. Error bars indicate SD. Additional data are provided in table 1A in the online supplementary file 2.