ABSTRACT
Background: The safety and effectiveness of vonoprazan-based Helicobacter pylori (H. pylori) eradication therapy in routine clinical practice, and patient characteristics that influence safety and effectiveness, have not been well investigated.
Methods: H. pylori-positive patients with gastric ulcer, duodenal ulcer, idiopathic thrombocytopenic purpura, history of endoscopic treatment of early gastric cancer, and gastritis were enrolled. Patients received vonoprazan 20 mg, amoxicillin (AMPC) 750 mg, and clarithromycin (CAM) 200–400 mg twice daily for 7 days for the first-line eradication. For the second-line eradication, vonoprazan, AMPC, and metronidazole (MTZ) 250 mg were administered. The incidence of adverse drug reactions (ADRs) and eradication rates were evaluated.
Results: The incidences of ADRs with vonoprazan/AMPC/CAM and vonoprazan/AMPC/MTZ were 3.22% (16/497) and 1.89% (1/53), respectively. Commonly reported ADRs were diarrhea, nausea, dysgeusia, feces soft, and rash. The eradication rates of the first-line therapy and the second-line therapy were 91.24% (427/468) and 95.45% (42/44), respectively. No notable differences in ADRs and eradication rates were observed when stratified by patient demographic characteristics.
Conclusion: No new safety concerns were observed, and the effectiveness of vonoprazan-based triple therapy was confirmed in routine clinical practice.
Trial registration: This study is registered at the Japan Pharmaceutical Information Center Clinical Trials Information (JapicCTI-153003).
1. Introduction
Helicobacter pylori (H. pylori) is a spiral, gram-negative, microaerophilic bacterium [Citation1]. H. pylori can cause infections in the stomach by various mechanisms, such as production of urease that catalyzes the hydrolysis of urea in the gastric mucus to yield ammonia which locally neutralizes gastric acid, and high motility trough flagella to move toward the more neutral pH of the gastric mucosa [Citation2,Citation3]. It has been reported that H. pylori infection may not only cause gastrointestinal diseases such as chronic gastritis, gastric ulcer, duodenal ulcer, gastric cancer, and gastric mucosa-associated lymphoid tissue (MALT) lymphoma, but also other non-gastrointestinal diseases such as diffuse large B-cell lymphoma, idiopathic thrombocytopenic purpura, iron deficiency anemia in children, and chronic urticaria [Citation4].
In the Guidelines for the Management of H. pylori infection, recommended first- and second-line treatment options for H. pylori eradication are triple therapy with a proton pump inhibitor (PPI) or vonoprazan plus amoxicillin (AMPC) and clarithromycin (CAM), and triple therapy with a PPI or vonoprazan plus AMPC and metronidazole (MTZ), respectively [Citation5]. However, first-line eradication rates achieved by PPI/AMPC/CAM have been decreasing due to an increase in resistance to CAM [Citation6].
Unlike conventional PPIs, vonoprazan inhibits gastric acid secretion by binding to a proton pump competitively with potassium ions without requiring activation by acid [Citation7,Citation8]. Although the binding of vonoprazan to the proton pump is reversible, the dissociation rate is low. In addition, since vonoprazan is highly basic, one of its characteristics is to remain in the acid production site of the gastric parietal cells for a long time to inhibit gastric acid production. In a clinical study that investigated the inhibitory effect of vonoprazan on gastric acid secretion by conducting 24-h intragastric pH monitoring, the holding time for an intragastric pH ≥4 following administration of vonoprazan 20 mg was significantly longer when compared to esomeprazole 20 mg and rabeprazole 10 mg. Thus, the result showed that vonoprazan inhibits gastric acid secretion promptly and persistently when compared to conventional PPIs [Citation9].
In a Japanese phase III study to investigate H. pylori eradication combination therapy with vonoprazan and antimicrobials in patients with gastric ulcer or duodenal ulcer scars, eradication rates achieved by the first-line eradication therapy with vonoprazan/AMPC/CAM and the second-line eradication therapy with vonoprazan/AMPC/MTZ were 92.6% and 98.0%, respectively [Citation10]. The safety profile of the first-line eradication therapy observed in this phase III study was similar to observations from clinical studies of vonoprazan involving patients with acid-related diseases (gastric ulcer, duodenal ulcer, reflux esophagitis) [Citation11,Citation12] and safety information described in the package insert of each antimicrobial used for eradication. The majority of adverse drug reactions (ADRs) associated with the second-line eradication therapy also occurred with the first-line eradication therapy, and those ADR profiles were not markedly different between the first- and second-line eradication therapies.
Efficacy and safety information from the phase III study were limited to patients with gastric ulcer or duodenal ulcer scars. Furthermore, information on patient characteristics that influence the safety and effectiveness of vonoprazan-based triple therapy is limited [Citation13]. We conducted a post-marketing surveillance study to investigate the safety and effectiveness of the combination therapy of vonoprazan-based triple therapy in routine clinical practice including patients with idiopathic thrombocytopenic purpura, history of endoscopic treatment of early gastric cancer, and gastritis.
2. Patients and methods
2.1. Study design
Patients prescribed vonoprazan-based triple therapy between September 2015 and February 2017 in study sites throughout Japan were enrolled in this prospective observational study. The target number of patients registered was set as 500.
The observation period included the period with triple therapy (7 days) and the period from the completion of triple therapy to the assessment of eradication. The assessment of eradication was conducted approximately 4 weeks to 2 months following the completion of triple therapy.
This study was conducted in accordance with Good Post-marketing Study Practice (GPSP). Because GPSP requires neither review of an Institutional Review Board nor written informed consent from patients, those were not mandatory in this study. The information on this study was registered in the Japan Pharmaceutical Information Center Clinical Trial Information (JapicCTI-153003).
2.2. Patients
Eligible patients were those with gastric ulcer, duodenal ulcer, gastric MALT lymphoma, idiopathic thrombocytopenic purpura, a history of endoscopic treatment of early gastric cancer, or H. pylori-infected gastritis scheduled to receive H. pylori eradication therapy for the first time, or those who failed to respond to first-line therapy (either vonoprazan/AMPC/CAM or PPI/AMPC/CAM) and scheduled to receive second-line eradication therapy. If patients included in this study failed to respond to vonoprazan/AMPC/CAM, they were eligible for inclusion in the study again as patients receiving vonoprazan/AMPC/MTZ. The data from patients who received both vonoprazan/AMPC/CAM and vonoprazan/AMPC/MTZ were analyzed separately as different individuals. Patients with a history of hypersensitivity to any of the components of vonoprazan, a contraindication for vonoprazan, and those under treatment with atazanavir sulfate or rilpivirine hydrochloride were excluded from this study.
2.3. Treatment
For vonoprazan/AMPC/CAM, patients received vonoprazan 20 mg, AMPC 750 mg, and CAM 200 mg orally, twice a day for 7 days. The dose of CAM could be increased up to 400 mg twice a day at the physician’s discretion. For vonoprazan/AMPC/MTZ, patients received vonoprazan 20 mg, AMPC 750 mg, and MTZ 250 mg orally, twice a day for 7 days. Concomitant medication was not restricted because this study was conducted under routine clinical practice.
2.4. Collected information
Collected information included hypersensitivity, concurrent medical conditions, previous eradication regimens received (for patients who failed in the previous vonoprazan/AMPC/CAM or PPI/AMPC/CAM), diagnosis of H. pylori infection (date of diagnosis and test method), dosage and administration of vonoprazan and antimicrobials used for triple therapy, and concomitant medications. For safety evaluation, the following information was collected: presence or absence of adverse events during the observation period; terms, outcome, and seriousness of adverse events; and the causality of adverse events with triple therapy. Any adverse events for which triple therapy could not be ruled out as the cause were defined as ADRs. The H. pylori eradication test method and assessment results were collected to evaluate their effectiveness.
2.5. Statistical analysis
The safety analysis set and the effectiveness analysis set were used. The safety analysis set was comprised of patients from whom case report forms (CRFs) were collected, but excluded those who did not receive vonoprazan, those who received the drugs before the start of their contracted period with the study site, those who were registered ≥6 days after the prescription day of triple therapy, and those for whom the occurrence of adverse events was unknown. The effectiveness analysis set was comprised of patients who were included in the safety analysis set, but excluded those whose eradication assessment was not conducted, those whose eradication assessment was conducted <28 days after the completion of triple therapy, those who received first-line therapy other than vonoprazan/AMPC/CAM, and those who received second-line therapy other than vonoprazan/AMPC/MTZ.
ADRs that occurred during the observation period were coded using MedDRA/J version 20.0 and classified according to System Organ Class (SOC) and Preferred Term (PT) to summarize the incidences of ADRs. Furthermore, the point estimates and the 95% confidence interval (CI) for incidences of ADRs were summarized by patient demographic characteristics and eradication regimens. A chi-squared test was also performed where applicable. The significance level was set as 5% two-sided.
For the effectiveness analysis, the percentage of patients who were proven to be H. pylori negative (i.e. eradication rate) was summarized by first- and second-line eradication therapies. Also, the point estimates and the 95% CI for eradication rates were summarized by patient demographic characteristics.
3. Results
3.1. Patient distribution and analysis sets
CRFs were collected from 554 of 560 eligible patients, excluding six patients for whom CRFs were not collected because it could not be confirmed whether they had received the drugs without visiting the study centers after the first prescription.
The safety analysis set included 550 patients from whom CRFs were collected, excluding four patients who did not receive vonoprazan, who were registered ≥6 days after the prescription day of triple therapy, or in whom the occurrence of adverse events was unknown. The effectiveness analysis set included 513 of the patients evaluable for the safety analysis, excluding 37 patients in whom eradication assessment was not conducted, for whom the eradication assessment was conducted <4 weeks after the completion or discontinuation of triple therapy, or who received first-line regimens other than vonoprazan/AMPC/CAM.
3.2. Patient demographics and treatment
Patient demographics in the safety analysis set are summarized in . Overall, 53.3% of the patients were female. The mean age was 58.7 years and the percentage of patients aged <65 years was 61.1% (). The most common target disease was H. pylori-infected gastritis (86.5%), followed by gastric ulcer (9.1%), duodenal ulcer (5.6%), idiopathic thrombocytopenic purpura (2.2%), and history of endoscopic treatment of early gastric cancer (2.2%). No patients with gastric MALT lymphoma were enrolled. For the diagnosis of H. pylori infection, 38.0% of the patients received anti-H. pylori antibody measurement and 30.4% received urea breath test (UBT).
Table 1. Patient demographics of safety analysis set.
Forty-eight patients received the second-line eradication therapy. The first-line eradication therapies for these patients were PPI/AMPC/CAM 800 mg (n = 27), PPI/AMPC/CAM 400 mg (n = 7), vonoprazan/AMPC/CAM 800 mg (n = 7), vonoprazan/AMPC/CAM 400 mg (n = 4), and unknown regimens (n = 3).
In the safety analysis set, 70.9% of the patients received vonoprazan/AMPC/CAM 400 mg, 19.5% received vonoprazan/AMPC/CAM 800 mg, and 9.6% received vonoprazan/AMPC/MTZ (). Four patients (0.7%) discontinued eradication therapies. The reason for discontinuation was the occurrence of adverse events for all of these patients (observed adverse events of each patient were diarrhea, diarrhea and dizziness, nausea, and ileus, respectively). For assessment of H. pylori eradication, 81.3% of the patients received UBT. Among nine patients who received anti-H. pylori antibody measurement, three received this test alone (H. pylori positive in one patient and negative in two patients).
Table 2. H. pylori eradication therapies in safety analysis set.
3.3. Safety
The overall incidence of ADRs was 3.09% (17/550) (). The incidences of commonly reported ADRs were 0.73% (4/550) each for diarrhea and nausea, 0.55% (3/550) for dysgeusia, and 0.36% (2/550) each for feces soft and rash. At the end of the observation period for each patient, all ADRs were recorded as either resolved or resolving. There were no reports of serious ADRs.
Table 3. Summary of ADRs reported in safety analysis set.
The incidences of ADRs stratified by patient demographic characteristics and eradication regimens are summarized in . Incidences of ADRs were higher in female patients than male patients (4.78% vs. 1.17%, p = 0.015). ADRs with an incidence of ≥1% observed in female patients were diarrhea and nausea (1.02% each), and no male patients had ADRs with incidences ≥1%. Incidences of ADRs were higher in patients aged ≥65 to <75 years than those aged <65 years and those aged ≥75 years (1.49% vs. 6.67% vs. 3.13%, p = 0.010). ADRs with incidence ≥1% observed in patients aged ≥65 to <75 years were nausea (2.00%), diarrhea and dysgeusia (1.33% each). Those in aged ≥75 years were dizziness, diarrhea and drug eruption (1.56% each), and no patients aged <65 years had ADRs with incidence ≥1%.
Table 4. Incidences of ADRs by patient demographics and eradication regimens.
The incidences of ADRs by triple eradication regimens were 3.22% (16/497) in patients who received vonoprazan/AMPC/CAM, and 1.89% (1/53) in those who received vonoprazan/AMPC/MTZ. ADRs were reported only in patients with H. pylori-infected gastritis (3.57% (17/476)).
3.4. Effectiveness
H. pylori eradication rates (95% CI) in patients treated with first- and second-line eradication therapies were 91.24% (88.30–93.64%) and 95.45% (84.53–99.44%), respectively (). There was no notable difference in H. pylori eradication rates stratified by patient demographic characteristics in both first-line and second-line eradication therapy ().
Table 5. H. pylori eradication rates by patient demographic characteristics.
4. Discussion
In this study, the safety and effectiveness of vonoprazan-based triple therapy in routine clinical practice were investigated, including patients who were not enrolled in the Japanese phase III study to investigate H. pylori eradication involving patients with gastric ulcer or duodenal ulcer scars [Citation10]. The overall incidences of ADRs in patients who received vonoprazan/AMPC/CAM and vonoprazan/AMPC/MTZ were 3.22% and 1.89%, respectively. These incidences in patients who received vonoprazan/AMPC/CAM were 20.4% (67/329), and the most commonly reported ADRs were diarrhea and dysgeusia in the Japanese phase III study [Citation10]. In patients who received vonoprazan/AMPC/MTZ, the overall incidence of ADRs was 16.0% (8/50), and the most commonly reported ADRs were diarrhea, flatulence, alanine aminotransferase increased, and aspartate aminotransferase increased [Citation10]. Our results showed that the incidences of ADRs did not exceed those reported from the Japanese phase III study, and there were no ADRs that were serious or in which the incidences were particularly high. Although the incidence of ADRs was significantly higher in females and patients aged ≥65 to <75 years, ADRs with incidence of ≥1% in these populations were also observed in other populations. Therefore, the results of this study suggested there were no new safety concerns.
H. pylori eradication rates were over 90% in both the first- and second-line eradication therapies in this study. These results were similar to the Japanese phase III study in which eradication rates of the first- and second-line eradication therapies were 92.6% (300/324) and 98.0% (49/50), respectively [Citation10]. Our results were also similar to the results of post-marketing research that investigated first-line eradication therapy with vonoprazan/AMPC/CAM and reported eradication rates of around 90% [Citation14–Citation17].
The post hoc analysis of the Japanese phase III study showed that the eradication rates of vonoprazan/AMPC/CAM were statistically significantly higher than lansoprazole/AMPC/CAM [Citation10]. It is considered important to raise the sensitivity of H. pylori to antimicrobials and the stability of antimicrobials by increasing intragastric pH to eradicate H. pylori [Citation18,Citation19]. The pharmacological properties of vonoprazan, such as more prompt onset and a longer duration of gastric acid secretion inhibition than conventional PPIs, may contribute to the difference in eradication rates between vonoprazan-based and PPI-based triple therapy.
For patient characteristics that affect PPI-based eradication therapy, smoking and diabetes have been reported to increase eradication failure [Citation20,Citation21]. In the current study, no notable difference in eradication rate was observed when stratified by patient demographic characteristics in first-line eradication therapy. Takara et al. reported that lifestyle-related factors did not impact the eradication rate of vonoprazan-based triple therapy in their retrospective analysis [Citation13]. These results support our findings.
One of the limitations of the present study is a lack of information on susceptibility to CAM, which was difficult to assess in routine clinical practice. Since the eradication rate of vonoprazan/AMPC/CAM was lower in CAM-resistant strains than in CAM-susceptible strains in the Japanese phase III study [Citation10], the other limitation for effectiveness assessment is methods used for detection of H. pylori. Anti-H. pylori antibody measurement was used in 38.0% of the patients and UBT was used in 38.0% for the diagnosis of H. pylori infection, while UBT was used in 81.3% of the patients for assessment of H. pylori eradication. Anti-H. pylori antibody measurement is a noninvasive and conventional method for H. pylori detection but difficult to prove ongoing infection due to immunological memory [Citation3]. The difference in methods used for H. pylori detection before and after the eradication therapy may influence the outcome of the therapy. Careful consideration may be needed to interpret our findings about eradication rates. In regard to the dose of CAM, the incidence of ADR was numerically greater in patients who received 800 mg/day than 400 mg/day, while the eradication rate was similar between two doses. Further information is needed to determine the optimal dose of CAM for vonoprazan-based triple therapy.
5. Conclusion
There were no new safety concerns observed for vonoprazan-based triple therapy in this study conducted within routine clinical practice. This study confirmed the effectiveness of vonoprazan-based triple therapy in real-world practice.
Author contributions
K Ashida contributed to data acquisition, data interpretation. Y Honda contributed data analysis, and data interpretation. K Sanada contributed study design. Y Takemura contributed data interpretation. S Sakamoto contributed to study design and data interpretation. All authors contributed to drafting and reviewing the manuscript critically, approved the final version, and agree to be accountable for all aspects of the work.
Declaration of interest
K Ashida received honoraria from Takeda Pharmaceutical Company Limited and Otsuka Pharmaceutical Company Limited. Y Honda, Y Takemura, and S Sakamoto are employees of Takeda Pharmaceutical Company Limited, and K Sanada is an employee of PRA Development Center KK. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
Acknowledgments
The authors sincerely appreciate the doctors who participated in this study to provide with precious data. Also, the authors appreciate Motoya Oshika, Japan Medical Office, Takeda Pharmaceutical Company Limited who managed this study, and Sho Sakui, Biostatistics, Development Center Japan, Takeda Pharmaceutical Company Limited, who conducted the statistical analyses.
Additional information
Funding
Related Research Data
References
- Warren JR, Marshall B. Unidentified curved bacilli on gastric epithelium in active chronic gastritis. Lancet. 1983;1(8336):1273–1275.
- Eaton KA, Brooks CL, Morgan DR, et al. Essential role of urease in pathogenesis of gastritis induced by Helicobacter pylori in gnotobiotic piglets. Infect Immun. 1991;59(7):2470–2475.
- Kusters JG, van Vliet AH, Kuipers EJ. Pathogenesis of Helicobacter pylori infection. Clin Microbiol Rev. 2006;19(3):449–490.
- Bravo D, Hoare A, Soto C, et al. Helicobacter pylori in human health and disease: mechanisms for local gastric and systemic effects. World J Gastroenterol. 2018;24(28):3071–3089.
- Guideline Committee of the Japanese Society for Helicobacter Research. Guidelines for the management of Helicobacter pylori infection in Japan: 2016 revised edition. Tokyo: Sentan Igaku Sha; 2016.
- Kawai T, Takahashi S, Suzuki H, et al. Changes in the first line Helicobacter pylori eradication rates using the triple therapy-a multicenter study in the Tokyo metropolitan area (Tokyo Helicobacter pylori study group). J Gastroenterol Hepatol. 2014;29(Suppl. 4):29–32.
- 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-methylmethanamin e monofumarate (TAK-438). J Pharmacol Exp Ther. 2011;339(2):412–420.
- Abadi ATB, Ierardi E. Vonoprazan and Helicobacter pylori treatment: a lesson from Japan or a limited geographic phenomenon? Front Pharmacol. 2019;10:316.
- Sakurai Y, Mori Y, Okamoto H, et al. Acid-inhibitory effects of vonoprazan 20 mg compared with esomeprazole 20 mg or rabeprazole 10 mg in healthy adult male subjects – a randomised open-label cross-over study. Aliment Pharmacol Ther. 2015;42(6):719–730.
- Murakami K, Sakurai Y, Shiino M, et al. Vonoprazan, a novel potassium-competitive acid blocker, as a component of first-line and second-line triple therapy for Helicobacter pylori eradication: a phase III, randomised, double-blind study. Gut. 2016;65(9):1439–1446.
- 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(2):240–251.
- 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(2):240–252.
- Takara Y, Endo H, Nakano R, et al. Smoking and drinking did not increase the failure of therapeutic Helicobacter pylori eradication by vonoprazan, clarithromycin, and amoxicillin. Digestion. 2019;99(2):172–178.
- Noda H, Noguchi S, Yoshimine T, et al. A novel potassium-competitive acid blocker improves the efficacy of clarithromycin-containing 7-day triple therapy against Helicobacter pylori. J Gastrointestin Liver Dis. 2016;25(3):283–288.
- Ozaki H, Harada S, Takeuchi T, et al. Vonoprazan, a novel potassium-competitive acid blocker, should be used for the Helicobacter pylori eradication therapy as first choice: a large sample study of vonoprazan in real world compared with our randomized control trial using second-generation proton pump inhibitors for Helicobacter pylori eradication therapy. Digestion. 2018;97(3):212–218.
- Sue S, Kuwashima H, Iwata Y, et al. The superiority of vonoprazan-based first-line triple therapy with clarithromycin: a prospective multi-center cohort study on Helicobacter pylori eradication. Intern Med. 2017;56(11):1277–1285.
- Suzuki S, Gotoda T, Kusano C, et al. The efficacy and tolerability of a triple therapy containing a potassium-competitive acid blocker compared with a 7-day PPI-based low-dose clarithromycin triple therapy. Am J Gastroenterol. 2016;111(7):949–956.
- Erah PO, Goddard AF, Barrett DA, et al. The stability of amoxycillin, clarithromycin and metronidazole in gastric juice: relevance to the treatment of Helicobacter pylori infection. J Antimicrob Chemother. 1997;39(1):5–12.
- Gustavson LE, Kaiser JF, Edmonds AL, et al. Effect of omeprazole on concentrations of clarithromycin in plasma and gastric tissue at steady state. Antimicrob Agents Chemother. 1995;39(9):2078–2083.
- Horikawa C, Kodama S, Fujihara K, et al. High risk of failing eradication of Helicobacter pylori in patients with diabetes: a meta-analysis. Diabetes Res Clin Pract. 2014;106(1):81–87.
- Suzuki T, Matsuo K, Ito H, et al. Smoking increases the treatment failure for Helicobacter pylori eradication. Am J Med. 2006;119(3):217–224.