First-Line Helicobacter pylori Eradication with Vonoprazan, Clarithromycin, and Metronidazole in Patients Allergic to Penicillin

Aim To assess the efficacy of 7-day first-line Helicobacter pylori eradication with vonoprazan (VPZ), clarithromycin (CAM), and metronidazole (MNZ) in patients with penicillin allergy. Methods Patients with penicillin allergy, diagnosed with Helicobacter pylori infection and did not have history of Helicobacter pylori eradication, were eligible for the study. Twenty patients were prospectively treated with 20 mg VPZ twice daily, 200 or 400 mg CAM twice daily, and 250 mg MNZ twice daily for 7 days. We also collected the data from 30 patients retrospectively treated with proton pump inhibitor (PPI), CAM, and MNZ. Safety was evaluated in patients completing an adverse effect questionnaire. Results Both the intention-to-treat and per-protocol effectiveness of VPZ-based eradication were 100% (95% CI: 86.1–100%; n = 20). The eradication rates of PPI-based regimen were 83.3% (95% CI: 65.3–94.4%) in the ITT and 82.7% (95% CI: 64.2–94.2%) in the PP analyses. Abdominal fullness was more frequent in VCM compared to PCM. However, all patients with VCM regimen had taken 100% of their course of medication. Conclusion Triple therapy with VPZ, CAM, and MNZ is well tolerated and effective for eradicating Helicobacter pylori in patients allergic to penicillin. This study was registered in the UMIN Clinical Trials Registry as UMIN000016335.


Study Design.
This was a first prospective and registered study of the efficacy and safety of a 7-day first-line H. pylori eradication regimen (VPZ/CAM/MNZ [VCM]) in patients with a documented allergy to penicillin. The protocol and informed consent forms were reviewed and approved by the Ethics Committee of Yokohama City University Hospital. This study was registered in the UMIN Clinical Trials Registry as UMIN000016335. After the approval of protocol and registration, this study was performed prospectively with written informed consent and Adverse Effects Questionnaires (later in detail) were filled by patients during therapy. We also collected retrospective data from our previous study of a 7-day PPI (LPZ) or esomeprazole (ESO/CAM/MNZ [PCM]) regimen in patients with penicillin allergy for comparison. The design of comparison between prospective VCM data and retrospective PCM data was approved and registered. It is important to note that PCM in a previous study was also conducted with written informed consent and by answering the Adverse Effects Questionnaire, and we used them in this study as retrospective data. The study was conducted in Yokohama City University (YCU) Hospital (Kanagawa, Japan) and the Institute for Adult Diseases, Asahi Life Foundation in Tokyo, Japan (Asahi Hospital). After approval of VPZ, the VPZ/CAM/ MNZ regimen was used, whereas before approval, the PPI/ CAM/MNZ regimen was used. This study is registered at https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi? recptno=R000018955. The registration identification number is UMIN000016335. This trial registry (http://www. umin.ac.jp/ctr/index/htm) is accepted by the International Committee of Medical Journal Editors (ICMJE).

Participants.
Male or female H. pylori-positive patients aged ≥ 20 years with a documented allergy to penicillin were eligible for inclusion. Penicillin allergy was diagnosed by physicians as being allergic to past penicillin derivatives. Subjects with any of the following were excluded: history of H. pylori eradication therapy; pregnancy or lactation; history of allergy to the drugs used (CAM and MNZ); severe liver dysfunction; severe renal dysfunction; severe heart dysfunction; and disqualification by their physicians. All of the eligible subjects were treated with the VCM regimen, including CAM-resistant H. pylori-infected patients.
2.3. Determination of H. pylori Status. H. pylori status was determined by detection of anti-H. pylori immunoglobulin G (HpIgG), a rapid urease test (RUT), culture, pathology (histology), or a carbon 13-labeled urea breath test ( 13 C-UBT). H. pylori eradication was primarily determined by a UBT with 100 mg UBT tablets (Otsuka Pharmaceutical Co. Ltd., Tokyo, Japan) using a cutoff of 2.5‰ or, in a few cases, with a stool H. pylori antigen test, both of which are considered standards [15,16]. For all of the participants, a follow-up UBT was performed after at least 4 weeks, and typically over 7 weeks, after completion of treatment to confirm successful eradication: 8.06 ± 2.39 weeks in VCM, 11.23 ± 4.83 weeks in PCM, and 9.96 ± 4.28 weeks in total. There is not a significant difference between VCM and PCM (p = 0 129). All subjects were asked to stop taking PPIs or VPZ from completion of treatment until the UBT. The UBT was performed by an external clinical inspection agency in all cases.

Treatment.
We analyzed first-line triple therapy with 20 mg bid VPZ in combination with 200 or 400 mg bid CAM plus 250 mg bid MNZ bid for 1 week (VCM regimen) ( Table 1). We also collected data on first-line triple therapy

Results
A total of 50 patients with penicillin allergy were enrolled. We also retrospectively evaluated 30 patients with a penicillin allergy in whom H. pylori eradication using first-line PCM therapy was successful. The PPIs used were LPZ (n = 20) and ESO (n = 10). Patient characteristics are shown in Table 1, and the drug withdrawal period was 11.2     Table 2. In 15% of cases, AEQ 3 abdominal fullness was reported. In 10% of cases, AEQ 3 nausea was reported. AEQ 3 anorexia, abdominal pain, and headache were each experienced in 5% of the cases. In terms of AEQ 2 or 3 adverse reactions, abdominal fullness was experienced in 30% cases; dysgeusia, nausea, abdominal pain, and fatigue were in 15% cases; anorexia, heart burn, and headache were in 10% cases; and diarrhea, belch, and mouth discomfort (others) were in 5% cases. There were no differences between VCM and PCM in AEQ 3. Only abdominal fullness in AEQ 2 or 3 was more frequent in VCM compared to PCM. However, all of the patients with VCM regimen had taken 100% of their course of medication.
Our result is in agreement with a previous report of the superiority of VPZ-based regimens in areas with a high rate of CAM resistance. The first-line ER of a VPZ/AMPC/ CAM (VAC) regimen in a CAM-resistant population (82%, n = 100) was higher than that of a PPI-(LPZ-) based regimen (40%) (n = 115) (p < 0 0001). We have confirmed this in real clinical practice that VAC exhibited an ER of 73.2% (n = 56) in a CAM-resistant population [18]. These results differ from those of PPI-based regimens; CAM resistance reduced the effectiveness to 55% (95% CI: 33-78%) according to a meta-analysis [19]. This study was conducted in areas of high CAM resistance; the H. pylori CAM resistance rate was~40% in YCU and was an average of 26% in hospitals in the Kanagawa area. Thus, the VCM regimen can be used in areas of low and high rates of CAM resistance, including Japan.
The first clinical implication of this study is the use of VCM instead of a 7-day PPI/MNZ/STFX regimen (PMS) in Japan, which was recently used for patients allergic to penicillin and showed an excellent ER of 100% (95% CI: 86.1-100.0%, n = 19) [11]. PMS as a third-line regimen also shows good efficacy (90.9%; 95% CI: 78.3-97.5%; n = 44) [23]. However, diarrhea (21.4% in the first-line study and 32.0% in the third-line study) and loose stool (35.7% in the firstline study and 68% in the third-line study) were reported as major adverse events, which were in higher rates than those of VCM (5% moderate AEQ and no severe diarrhea according to AEQ score).
The second clinical implication is the possibility of VPZ-based concomitant therapy and a bismuth-based VCM regimen [24,25]. Both this study and the VPZ phase III study [13] suggest the utility of VPZ-based regimens in CAMresistant populations.
Our results must be interpreted with the following limitations in mind. First, the sample size was small and study design was not RCT. However, 3-7% of patients are allergic to penicillin in Japan [26] and elsewhere [27]; therefore, a large-scale study with VCM regimen is difficult in a limited period of time after approval of VPZ. Second, we could not assess resistance to CAM and MNZ in the majority of cases (10/13). One case had the following minimum inhibitory concentration values: CAM 16 mg/L, AMPC 0.5 mg/L, STFX 0.25 mg/L, MNZ 4 mg/L, but eradication was successful in this patient. The other two cases were susceptible (AMPC < 0.03, CAM < 0.03, STFX 0.06, and MNZ 2; AMPC < 0.03, CAM < 0.03, STFX < 0.03, and MNZ 2); these patients also experienced successful eradication. Further study of VCM regimen with CAM and MNZ resistance information in all cases is needed. During manuscript preparation, a similar study was published. This reported an ER of the VCM regimen in patients with penicillin allergy of 92.9%. The authors also suggested that VCM could be used in such patients [28]. Our study is important, because our study is the first prospective as well as registered study of VCM regimen, and our study used the same Adverse Effect Questionnaire, which is available to be compared with PCM.

Conclusions
Our data demonstrated that 7-day VCM therapy has an excellent ER and safety profile in patients with a penicillin allergy in areas of a high rate of CAM resistance.

Ethical Approval
All of the studies were performed in accordance with the Declaration of Helsinki and the "Ethical Guidelines for Medical and Health Research Involving Human Subjects" (March 2005, the Japanese Ministry of Health, Labor, and Welfare) and were registered at UMIN-CTR, a standard registry according to the International Committee of Medical Journal Editors (ICMJE), with the identifier UMIN000016335. The protocol was approved by the Institutional Review Board of each study site. The study was reviewed and approved by the Ethics Committee/Institutional Review Board of Yokohama City University Hospital, Japan (no. B150108015).

Consent
All study participants provided informed written consent prior to study enrollment.

Conflicts of Interest
None of the authors has a conflict of interest to declare.

Authors' Contributions
Soichiro Sue and Shin Maeda designed the research; Soichiro Sue, Nobumi Suzuki, Wataru Shibata, Tomohiko Sasaki, Hiroaki Yamada, Hiroaki Kaneko, Toshihide Tamura, Tomohiro Ishii, Masaaki Kondo, and Shin Maeda performed the research; Soichiro Sue and Nobumi Suzuki analyzed the data; and Soichiro Sue wrote the paper.