DOI: 10.1111/hel.

12456

ORIGINAL ARTICLE

Vonoprazan-­ vs proton-­pump inhibitor-­based first-­line 7-­day

triple therapy for clarithromycin-­susceptible Helicobacter pylori:
A multicenter, prospective, randomized trial

Soichiro Sue1 | Marina Ogushi2 | Isao Arima3 | Hirofumi Kuwashima2 | 

Satoshi Nakao3 | Makoto Naito2 | Kazuo Komatsu3 | Hiroaki Kaneko1 | 
Toshihide Tamura1 | Tomohiko Sasaki1 | Masaaki Kondo1 | Wataru Shibata4 | 
Shin Maeda1

1
Department of Gastroenterology, Yokohama
City University Graduate School of Medicine,
Yokohama, Japan
2
Department of Gastroenterology, Yokohama
Hodogaya Central Hospital, Yokohama, Japan
3 with clarithromycin (CAM)-­susceptible Helicobacter pylori in a phase III study, whereas
Department of Gastroenterology, Yokosuka
City Hospital, Yokosuka, Kanagawa, Japan
4
Advanced Medical Research Center,
Yokohama City University, Yokohama, Japan
Correspondence
Shin Maeda, Department of Gastroenterology,
Yokohama City University Graduate School of
Medicine, Yokohama, Japan.
Email: shinmaeda2-gi@umin.ac.jp
Funding information
This study was supported by Yokohama City
University (basic research expenditure).
Abstract
Background: The eradication rate of vonoprazan-­based first-­line triple therapy (com-
bined with clarithromycin and amoxicillin) (V-­AC) was reported to be 97.6% in patients
our real-­
world, prospective, multicenter cohort study yielded an eradication rate
<90%.
Objective: To validate the eradication rate of V-­AC using CAM-­susceptible testing in
a multicenter, prospective, randomized trial.
Methods: We included 147 treatment-­naïve H. pylori-­positive patients [41 with CAM-­
resistant infections and 106 with CAM-­susceptible infections]. The CAM-­susceptible
group patients were randomized to either the V-­AC group (vonoprazan 20 mg bid,
amoxicillin 750 mg bid, and clarithromycin 200 or 400 mg bid) or PPI-­AC group (lanso-
prazole 30 mg, rabeprazole 10 mg, or esomeprazole 20 mg bid; amoxicillin 750 mg bid;
and clarithromycin 200 or 400 mg bid). All CAM-­resistant H. pylori were eradicated by
V-­AC, as measured by the urea breath test around 8 weeks after eradication. Safety
was evaluated by patient questionnaires.
Results: The intention-­to-­treat and per-­protocol eradication rates of V-­AC in the
CAM-­susceptible H. pylori-­infected patients were 87.3% (95% confidence interval
75.5%-­94.7%) and 88.9% (77.4%-­95.8%). The respective eradication rates of PPI-­AC
were 76.5% (62.5%-­87.2%) and 86.7% (73.2%-­94.9%). No significant difference was
observed between the V-­AC and PPI-­AC regimes in terms of the intention-­to-­treat
(P = .21) or per-­protocol (P = .77) analyses. The questionnaire scores did not differ sig-
nificantly between the groups. Both the intention-­to-­treat and per-­protocol eradica-
tion rates of V-­AC in the CAM-­resistant patients were 82.9% (67.9%-­92.8%).
Conclusion: The eradication rate of V-­AC treatment in the CAM-­susceptible H. pylori-
infected patients was <90%, as was that by PPI-­AC, thus V-­AC is not ideal regimen in
CAM-­susceptible H. pylori. However, the 82.9% eradication rate of V-­AC in the CAM-­
resistant infections may indicate the potential of V-­AC with modified dose, dosing in-
terval, and treatment duration. (UMIN000016337).

Helicobacter. 2017;e12456. wileyonlinelibrary.com/journal/hel © 2017 John Wiley & Sons Ltd  |  1 of 8
https://doi.org/10.1111/hel.12456
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KEYWORDS
7-day triple therapy, clarithromycin-susceptible, Helicobacter pylori eradication, vonoprazan
1 |  INTRODUCTION
Helicobacter pylori (H. pylori) eradication reduces the incidence of gas-
tric cancer1; the 40% risk reduction associated with H. pylori could be
improved to 75% if eradication were complete and sustained.2 Thus,
effective H. pylori eradication is important. The eradication rate of the
7-­day proton-­pump inhibitor (PPI)/amoxicillin (AMPC)/clarithromycin
(CAM) “legacy” triple therapy (PPI-­AC) for H. pylori is inadequate in
many countries.3 Antibiotic resistance is the main factor compromising
triple therapy, reducing the eradication rate from 88% to 18% [for PPI-­
based therapy according to a 20-­study meta-­analysis4]. In Japan, the
eradication rate of H. pylori by PPI-­AC therapy decreased from 90% in
2001 to 75.9% in 2015, accompanied by increasing CAM resistance of
5
H. pylori, from <20% in 2001 to 33% in 2015.
Vonoprazan (VPZ), a member of a novel class of acid suppres-
sants (potassium-­competitive acid blockers), has been used to treat
H. pylori infections in Japan since February 2015. In a phase III, ran-
domized, double-­blind study, the eradication rate of VPZ/AMPC/
CAM (V-­AC regimen) (92.6%; n = 324) was found to be noninferior
to that of lansoprazole (a PPI)/AMPC/CAM (LAC regimen) (75.9%;
n = 320; P < .001). On subgroup analysis of CAM-­resistant H. pylori,
the eradication rate of V-­AC (82.0%; n = 100) was significantly higher
(P < .0001) than that of LAC (40.0%; n = 115), but no significant dif-
ference was evident in the CAM-­susceptible H. pylori group (V-­AC,
97.3%, n = 224 vs LAC, 96.0%, n = 205).6 However, reasons for this
finding could be that the subjects had histories of gastric or duodenal
13
ulcers, the timing of the C-­urea breath test (UBT) at just 4 weeks
after eradication may be associated with false-­negatives, and physi-
cians assessed the safety.
A recent, multicenter, randomized trial showed that LAC triple
therapy in CAM-­susceptible patients yielded an H. pylori eradication
rate of 88% after 2 weeks.7 Other studies also found that the H. pylori
eradication rates of PPI-­AC used to treat CAM-­susceptible infections
8
were approximately 90%. However, it remained unclear whether
the eradication rate of V-­AC for CAM-­susceptible H. pylori infections
under conditions similar to those of a previous study (all patients in-
fected with H. pylori; the UBT was performed ~8 weeks after the drug
regimen concluded) was > or <90%.
In addition, the eradication rate of V-­
AC used to treat CAM-­
resistant H. pylori infections requires confirmation. It is important to
determine whether the eradication rate of V-­AC for CAM-­resistant
infections is >90%,9 because VPZ or PPI/AMPC/metronidazole (MTZ)
7-­day triple therapy as a first-­line eradication treatment of CAM-­
resistant H. pylori infections in Japan has been recommended by the
Japanese Society of Gastroenterology but is not covered by the na-
10
tional insurance scheme. If 7-­day V-­AC treatment of CAM-­resistant
infections yields an eradication rate <90%, we suggest that, ethically,
V-­AC should be used instead of VPZ or the PPI/AMPC/MTZ regimen,
which is associated with a high eradication rate in Japanese regions
with low MTZ resistance rates.11
Thus, in this study, the efficacy and safety of V-­AC were compared
with those of PPI-­AC for treatment of CAM-­susceptible H. pylori in-
fections and were confirmed for treatment of CAM-­resistant H. pylori
infections.
2 | METHODS
2.1 | Study design
We performed a prospective, multicenter, open-­
label, randomized
trial in patients infected by CAM-­susceptible or CAM-­resistant H. py-
lori. The efficacy and safety of VPZ-­based first-­line eradication were
evaluated for CAM-­resistant H. pylori and compared with those of
PPI-­based first-­line eradication of CAM-­susceptible H. pylori. The drug
regimens used were VPZ-­based 7-­day triple therapy (VPZ, AMPC, and
CAM) and PPI-­based 7-­day triple therapy (lansoprazole, rabeprazole,
or esomeprazole; AMPC; and CAM). The study was conducted by the
Yokohama City University Hospital, Yokohama Hodogaya Central
Hospital, and Yokosuka City Hospital in Kanagawa in Japan between
February 2015 and October 2016. The study was performed in ac-
cordance with the Declaration of Helsinki and the “Ethical Guidelines
for Medical and Health Research Involving Human Subjects” (March
2005, Japanese Ministry of Health, Labor, and Welfare) and was
registered in the UMIN-­CTR [a standard registry maintained by the
International Committee of Medical Journal Editors (ICMJE)] with the
identifier UMIN000016337. The protocol was approved by the insti-
tutional review boards of each hospital.
2.2 | Participants
Male and female H. pylori-­
positive patients (described below)
≥20 years of age with available information regarding their H. pylori
CAM status were eligible for inclusion. The exclusion criteria were
1, any history of H. pylori eradication therapy; 2, pregnancy or lacta-
tion; 3, a history of allergy to any drug used; 4, severe liver, renal,
or heart dysfunction; and 5, disqualification by a personal physician.
Written informed consent was obtained from all patients before the
trial commenced.
2.3 | Determination of H. pylori status
The H. pylori status of all participants was determined by 1, detection
of anti-­H. pylori IgG antibodies; 2, the rapid urease test; 3, bacterial
culture; 4, pathology (histology); or 5, the UBT. Endoscopy and bi-
opsy samples from all subjects were cultured and subjected to the
agar ­dilution test.
SUE et al.
To confirm successful eradication, UBTs employing UBIT 100-­mg tab-
lets (Otsuka Pharmaceutical Co., Ltd. Kanda Tsukasa-machi, Chioda-ku,
Tokyo, Japan) were performed at least 4 weeks after the drug regimens
concluded (typically around 8 weeks). All subjects were instructed not to
take PPIs or VPZ from the time of treatment completion until the UBT.
All UBTs were performed by an external agency; all technicians were
blinded to the treatment ­regimens and the nature of this study.
2.4 | Susceptibility of H. pylori to antimicrobial
agents
Gastric biopsy specimens collected from both greater gastric cor-
pus and antrum during endoscopy were inoculated into H. pylori
transport medium and transported in 4°-­9°. Culture, susceptibil-
ity testing by agar dilution test and determination of the minimum
inhibitory concentration were performed by clinical inspection
agency; in all cases, they were blinded to the clinical information
and the presence of this research. Culture was performed with
blood agar medium for Helicobacter with addition of 10% CO2 at 35°
for 7 days. Identification of H. pylori was defined as Gram-­negative
bacillus with catalase test positive, oxidase test positive, and urease
test positive. When culture was positive for H. pylori, the minimum
inhibitory concentrations (MICs) of CAM and AMPC to H. pylori
were determined by the agar plate dilution method in accordance
with the guidelines established by the NCCLS Guidelines M100-­S9.
Mueller-­Hinton agar (5% horse blood) was used with addition of
10% CO2 at 35° for 72 hours. Concentration was measured be-
tween 0.03 and 128 μg/mL. The CAM-­
resistant breakpoint and
AMPC-­resistant breakpoint were defined as ≥1.0 and ≥0.5 mg/L, in
12
line with previous reports.
2.5 | Treatment
Patients infected with CAM-­susceptible H. pylori were randomly as-
signed to 2 regimens: V-­AC triple therapy (VPZ 20 mg bid, amoxicillin
750 mg bid, and clarithromycin 200 or 400 mg bid for 7 days; n = 55)
or PPI-­AC triple therapy with PPI (lansoprazole 30 mg, rabeprazole
10 mg, or esomeprazole 20 mg bid; amoxicillin 750 mg bid; and
clarithromycin 200 or 400 mg bid for 7 days; n = 51).
Allocation ratio of V-­AC or PPI-­AC in CAM-­susceptible H. pylori
was 1:1. Patients infected with CAM-­resistant H. pylori were treated
with the V-­AC regimen (n = 41).
Proton-­pump inhibitors used in this study: lansoprazole, esome-
prazole, and rabeprazole were different in the effects on intragastric
pH as Kirchheiner showed.13 However, we treated these PPIs with
30 mg bid (60 mg/d) dose of lansoprazole, 20 mg bid (40 mg/d) dose
of esomeprazole, or 10 mg bid (20 mg/d) dose of rabeprazole in the
same group, because previous RCTs showed no difference of eradica-
tion rate between lansoprazole 30 mg bid (60 mg/d) and rabeprazole
10 mg bid (20 mg/d),14 in addition, between lansoprazole 30 mg bid
(60 mg/d) and esomeprazole 20 mg bid (40 mg/d).15 This treatment of
PPIs also supported by our previous data.16 We need to emphasize the
standard dose of PPIs in this study, because previous meta-­analysis
|
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concluded high-­dose PPI seems more effective than standard dose for
curing H. pylori infection in 7-­day triple therapy.17
We included patients treated with CAM 200 and 400 mg bid in the
same group, because a phase III trial revealed no significant difference
in the eradication rate between the 2 doses.6 In addition, our previous
data also showed dose of CAM did not affect the results.16
2.6 | Randomization and blinding
The random allocation was performed in the order of registration.
We used easily accessible web-­based minimization random alloca-
tion system “QMinim Online Minimization” which was explained in
the paper.18 Each physician enrolled participants and “QMinim Online
Minimization” assigned participants to interventions. Each physician
enrolled participants and “QMinim Online Minimization” assigned
participants to interventions. Randomization was performed using
the minimization method by reference to age and sex. This trial was
designed as open-­labeled, because the primary endpoint eradication
rate of H. pylori is objective data.
2.7 | Procedures
A physician completed all study registration forms, recording sex, age,
smoking status, endoscopic findings, antimicrobial susceptibility test
results (obtained using the standard agar plate dilution method), CAM
status, the drug regimen prescribed, and the start date of therapy.
After therapy, the efficacy of H. pylori eradication was assessed by the
UBT using a cutoff of 2.5%. A case report form was then completed,
which included the date and result of the UBT, the extent of treat-
ment compliance, any adverse events, and confirmation of VPZ or PPI
washout after eradication (at the time of the UBT). The interventions
of each patient can be confirmed by medical records and prescription
which can search in electronic medical records system of each cite.
An adverse effect questionnaire (AEQ) was completed by all patients
during therapy (except 5 who dropped out) and was collected at the
first visit after therapy. The AEQ contained 13 questions exploring
diarrhea, dysgeusia, nausea, anorexia, abdominal pain, heartburn, urti-
caria, headache, abdominal fullness, eructation, vomiting, fatigue, and
other symptoms. The possible answers were none (score of 0), weak
(1), moderate (2), or strong (3), similar to our previous study.16 The
data of registration form, case report, and adverse effect question-
naire were collected in each study cite. And the data sets were inte-
grated at the data center of this study at Yokohama City University
and analyzed.
The primary outcomes were the first-­
line H. pylori eradication
rates of CAM-­susceptible H. pylori afforded by the 2 regimens (V-­AC
and PPI-­AC) and that of CAM-­resistant H. pylori by V-­AC. The second-
ary outcome was regimen safety, as evaluated using the AEQ.
2.8 | Sample size calculation
Patient numbers were planned by reference to VPZ phase III data re-
vealing CAM-­susceptible H. pylori eradication rates of 97.6% afforded by
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VPZ/AMPC/CAM and 97.3% afforded by PPI/AMPC/CAM. We added

10% margins to the patient numbers. The number of patients needed
in each group with CAM-­susceptible H. pylori infections was 53 (106
total) to achieve a power of 80% with a type I error of 0.05. Using the
CAM-­resistant infection rate of 33% reported in Japan, we calculated the
total number of patients needed as 160 (with either CAM-­susceptible or
CAM-­resistant infections). Enrollment was terminated at 160 patients.

2.9 | Statistical analysis
The eradication rates of each group were compared using both
intention-­to-­treat (ITT) and per-­protocol (PP) analyses. Categorical
data were compared using Fisher’s exact test, as appropriate.
Continuous data were compared using Student’s t test. All P-­values
were two-­tailed, and the level of statistical significance was set at .05.
The frequencies and two-­sided 95% confidence intervals (CIs) of the
primary endpoints were calculated for each group. The difference in
the eradication rates between the V-­AC and PPI-­AC treatments of
CAM-­susceptible infections was evaluated using Fisher’s exact test
(with two-­sided 95% CIs) for both the ITT and PP analyses. All sta-
tistical analyses were performed using SPSS software (ver. 24) (IBM,
Armonk, New York, USA). All authors had access to all study data and
reviewed and approved the final manuscript.
3 |  RESULTS
3.1 | Study flow
The study flow is summarized in Figure 1. The periods of recruitment
and follow-­up are from February 2015 to October 2016. A total of
160 patients with H. pylori infection who met the eligibility criteria
were enrolled. Of these, 147 were evaluated in terms of CAM status;
106 had CAM-­susceptible and 41 CAM-­resistant H. pylori infections.
The CAM-­susceptible patients were randomized into 2 subgroups:
55 treated with the V-­AC regimen and 51 with the PPI-­AC regimen.
Details of PPIs were 42 patients with lansoprazole, 5 patients with
esomeprazole, and 4 patients with rabeprazole. All 41 patients with
CAM-­
resistant infections received the V-­
AC regimen. One V-­
AC-­
treated and 4 PPI-­AC-­treated CAM-­susceptible patients were lost to
follow-­up (n = 4, lansoprazole). Two PPI-­AC-­treated CAM-­susceptible
patients underwent interrupted eradication because of heart failure
(n = 1, lansoprazole) or adverse events (dysgeusia, AEQ score of 3;
diarrhea, score of 2; and anorexia, score of 2) (n = 1, esomeprazole). In
total, 54 patients treated with V-­AC and 45 treated with PPI-­AC (37
patients with lansoprazole, 4 patients with esomeprazole, and 4 pa-
tients with rabeprazole) in the CAM-­susceptible group and 41 treated
with V-­AC in the CAM-­resistant group completed their regimens and
were evaluated.
3.2 | Baseline characteristics
The demographic and other baseline characteristics of the CAM-­
susceptible patients are summarized in Table 1. The 2 CAM-­
S Table 3, but the number of CAM 400 mg bid (800 mg/d) was small.
F I G U R E   1   Patient flow chart. V-­AC, VPZ/AMPC/CAM 1-­
wk eradication therapy; PPI-­AC, PPI (lansoprazole, rabeprazole,
or esomeprazole)/AMPC/CAM 1-­wk eradication therapy; MIC,
minimum inhibitory concentration as determined by the agar dilution
test; AEQ, adverse effect questionnaire
subgroups were demographically similar (V-­
AC: females 32%, age
64.3 ± 12.3 years; PPI-­AC: females 31%, age 61.9 ± 13.3 years) and
did not differ significantly in terms of the clinical data (smoking rate,
CAM dose, endoscopic findings, and drug withdrawal period). All pa-
tients were AMPC-­susceptible, and minimum inhibitory concentration
was less than 0.12 mg/L. It is important that the drug withdrawal pe-
riod prior to the UBT when evaluating eradication is ~8 weeks. Data
on patients in the V-­AC-­treated CAM-­resistant group are also sum-
marized in Table 1.
3.3 | Efficacy
As shown in Figure 2, the ITT and PP analyses of eradication rate of
V-­AC in the CAM-­susceptible subgroup were 87.3% (95% CI = 75.5%-­
94.7%, 48/55) and 88.9% (95% CI = 77.4%-­95.8%, 48/54), respec-
tively. The figures for the PPI-­AC for CAM-­susceptible subgroup were
76.5% (95% CI = 62.5%-­87.2%, 39/51) and 86.7% (95% CI = 73.2%-­
94.9%, 39/45) and those for the V-­AC for CAM-­resistant group 82.9%
(95% CI = 67.9%-­92.8%) for both the ITT and PP analyses. No sig-
nificant difference was observed between the V-­AC and PPI-­AC for
CAM-­susceptible subgroups in terms of either the ITT (P = .21) or PP
(P = .77) analyses. The differences were 10.8% (95% CI = −3.8% to
25.4%) for the ITT analysis and 2.2% (95% CI = −10.8% to 15.2%) for
the PP analysis.
The details of eradication rates with each PPIs and each CAM
doses were shown in Tables 2 and 3, respectively. Intention-­to-­treat
analyses were 73.8% (n = 42) with lansoprazole, 80% (n = 5) with es-
omeprazole, and 100% (n = 4) with rabeprazole. Per-­protocol analyses
were 83.7% (n = 37) with lansoprazole, 100% (n = 4) with esome-
prazole, and 100% (n = 4) with rabeprazole. In per-­protocol analyses
of CAM 200 mg bid (400 mg/d) dose, eradication rates of V-­AC and
PPI-­AC regimens for CAM-­susceptible H. pylori were 90.7% (n = 43)
and 90.2% (n = 41), respectively. Other results are presented in
SUE et al. |
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T A B L E   1   Baseline characteristics
CAM-­susceptible CAM-­resistant

V-­AC PPI-­AC P V-­AC

Age 64.3 ± 12.3 61.9 ± 13.3 .33 64.0 ± 11.4

Male, % 68.0 69.0 1 51.2
Smoking, % 5.4 7.8 .45 12.2
CAM 200 bid, % 80.0 90.2 .18 87.8
Endoscopic findings, %
Gastroduodenal ulcer 1.8 11.8 4.9
Gastric cancer 0 2.0 0
Gastric adenoma 0 3.3 .08 0
MALT 1.8 0 0
Gastritis only 96.4 86.2 95.1
Diagnosis of infection
Culture 100 100 1 100
CAM resistance, % 0 0 1 100
AMPC resistance, % 0 0 1 0

V-AC: Vonoprazan/AMPC/CAM 1-­wk eradication therapy, PPI-AC: PPI (LPZ, RPZ, or ESO)/AMPC/
CAM 1-­wk eradication therapy, CAM 200 bid, %: percentage of CAM 200 mg twice per day (400 mg/d)
against CAM 400 mg twice per day (800 mg/d), Endoscopic findings: all participants underwent endos-
copy before eradication therapy.

T A B L E   2   Eradication rates with each PPI

Intention-­to-­treat Per-­protocol

Lansoprazole-­AC 73.8% (n = 42) 83.7% (n = 37)

Esomeprazole-­AC 80.0% (n = 5) 100% (n = 4)
Rabeprazole-­AC 100% (n = 4) 100% (n = 4)
Total (PPI-­AC) 76.5% (n = 51) 86.7% (n = 45)

Lansoprazole-­AC: 1-­wk triple therapy with 30 mg bid (60 mg/d) dose of

lansoprazole, AMPC, and CAM, Esomeprazole-­AC: 1-­wk triple therapy
with 20 mg bid (40 mg/d) dose of esomeprazole, AMPC, and CAM,
Rabeprazole-­AC: 1-­wk triple therapy with 10 mg bid (20 mg/d) dose of ra-
beprazole, AMPC, and CAM, PPI-­AC: Lansoprazole-­AC, Esomeprazole-­AC,
or Rabeprazole-­AC.

F I G U R E   2   Efficacies of 2 regimens (V-­AC and PPI-­AC) against
CAM-­susceptible Helicobacter pylori and of the V-­AC regimen
against CAM-­resistant H. pylori. V-­AC, VPZ/AMPC/CAM 1-­wk
eradication therapy; PPI-­AC, PPI (lansoprazole, rabeprazole, or
esomeprazole)/AMPC/CAM 1-­wk eradication therapy; CAM-­
susceptible, CAM-­susceptible H. pylori; CAM-­resistant, CAM-­resistant
H. pylori; ITT, intention-­to-­treat analysis; PP, per-­protocol analysis
3.4 | Safety
The frequencies of adverse effects during therapy are shown in
Table 4. No significant difference in any AEQ score was evident
between the V-­AC and PPI-­AC subgroups of the CAM-­susceptible
group. One patient in the PPI-­AC subgroup of the CAM-­susceptible
group withdrew because of adverse events (dysgeusia, AEQ score of
3; diarrhea, score of 2; and anorexia, score of 2).
4 | DISCUSSION
We found that the eradication rate of V-­AC for CAM-­susceptible
H. pylori was <90%, similar to that of PPI-­AC, and the eradication rate
of V-­AC for CAM-­resistant H. pylori was 82%. No significant differ-
ence in the frequency of adverse events was evident between pa-
tients treated with V-­AC and those treated with PPI-­AC. This is the
first registered prospective, parallel-­group, randomized trial evaluat-
ing VPZ-­based triple therapy according to CAM-­susceptible H. pylori
status (Figure 1).
All subjects were infected with H. pylori, unlike those of the pre-
vious VPZ phase III trial (who had histories of gastric or duodenal
ulcers).6 This is the first prospective randomized trial to feature CAM-­
susceptible testing; a CAM-­susceptible status greatly improves the ef-
fectiveness of triple regimens containing CAM.19 Only a randomized
design can eliminate all confounders (including unknowns). Thus, this
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T A B L E   3   Eradication rates with each

CAM-­susceptible CAM-­resistant
dose of CAM
V-­AC PPI-­AC V-­AC

Intention-­to-­treat
CAM 200 bid 88.6% (n = 44) 80.4% (n = 46) 86.1% (n = 36)
CAM 400 bid 81.8% (n = 11) 40.0% (n = 5) 60.0% (n = 5)
Total 87.3% (n = 55) 76.5% (n = 51) 82.9% (n = 41)
Per-­protocol
CAM 200 bid 90.7% (n = 43) 90.2% (n = 41) 86.1% (n = 36)
CAM 400 bid 81.8% (n = 11) 50.0% (n = 4) 60.0% (n = 5)
Total 88.9% (n = 54) 86.7% (n = 45) 82.9% (n = 41)

CAM: clarithromycin, CAM 200 bid: CAM 200 mg twice per day (400 mg/d), CAM 400 bid: CAM
400 mg twice per day (800 mg/d), V-­AC: Vonoprazan/AMPC/CAM 1-­wk eradication therapy, PPI-­AC:
PPI (LPZ, RPZ or ESO)/AMPC/CAM 1-­wk eradication therapy.

study is more significant than all others that appeared after VPZ ap- one retrospective propensity score-­
matching study lacking CAM-­
proval [our earlier prospective study featuring CAM-­susceptible test- susceptible testing,22 and 7 retrospective studies lacking CAM-­
ing,14 2 retrospective studies featuring CAM-­susceptible testing,20,21 susceptible testing].

T A B L E   4   Adverse effects by
CAM-­susceptible CAM-­resistant
questionnaire
V-­AC (%) PPI-­AC (%) P (%) V-­AC (%)

Any (score 1, 2 or 3)
Diarrhea 11 43 .23 18
Dysgeusia 19 10 .45 16
Nausea 8 5 1 8
Anorexia 11 10 1 11
Abdominal pain 11 19 .68 11
Heart burn 4 5 1 16
Hives 0 5 1 2
Headache 4 19 .15 16
Abdominal fullness 30 10 .15 29
Belch 15 5 .36 13
Vomiting 4 0 1 0
General malaise 15 5 .36 13
Other 4 5 1 2
Score 3
Diarrhea 0 10 .18 0
Dysgeusia 0 5 .44 5
Nausea 4 0 1 0
Anorexia 4 0 1 0
Abdominal pain 4 0 1 0
Heart burn 0 0 1 2
Hives 0 0 1 2
Headache 0 0 1 0
Abdominal fullness 0 0 1 5
Belch 0 0 1 5
Vomiting 4 0 1 0
General malaise 4 0 1 0
Other 0 5 1 0
SUE et al.
We found that V-­AC 7-­day triple therapy of CAM-­susceptible infec-
9
tions scored as grade C (fair) (85%-­89%) using the criteria of Graham,
consistent with previous studies. We emphasize 2 points: 1, the <90%
eradication rate of PPI-­
AC in patients infected with CAM-­
susceptible
H. pylori is similar to that of most previous studies3,7,8,23; and 2, the eradica-
tion rates of the V-­AC and PPI-­AC regimens in CAM-­susceptible H. pylori-­
infected patients did not differ in the VPZ phase III study.6 We suggest
that the reported eradication rate of 97.3% (95% CI = 93.8-­99.1, n = 185)
of the lansoprazole/AMPC/CAM regimen in CAM-­susceptible patients is
abnormally high, compared with the eradication rates afforded by PPI-­AC
in similar patients in the present study (76.5%, 95% CI = 62.5%-­87.2%,
n = 51), our prospective multicenter cohort study (84.2%, 95% CI = 78.4-­
89.1, n = 197),16 and two recent 2-­week randomized controlled trials (89%,
7,12
95% CI = 83.9-­92.9, n = 209) (90%, 95% CI = 82.7-­94.9, n = 109).
As for past PPI-­AC studies in Japan, there are 2 PPI-­AC RCTs indi-
cating the eradication rate of PPI-­AC regimen in CAM-­susceptible pa-
tients. On the other hand, many PPI-­AC RCTs in Japan were without
susceptibility testing, and some RCTs only showed the percentage of
CAM-­
susceptible or CAM-­
resistant. One study showed 77.6% (95%
CI = 72%-­82%, n = 232) in CAM-­susceptible,24 whereas the other study
showed 94% (95% CI = 88.9-­96.6, n = 185) in CAM-­susceptible25 with
same doses of PPI-­AC regimens used in this study. The author of 94% re-
sult mentioned “slightly higher than those in comparable studies in Japan”
in the discussion of the paper. We found that high results of 97.3% in VPZ
phase III or above-­mentioned 94% are company funding research. It is
important that without company funding RCT showed similar results to
real-­world data, whereas company funding RCT showed higher results.
Thus, the high V-­AC eradication rate reported previously in CAM-­
susceptible H. pylori-­infected patients (97.6%, 95% CI = 94.4-­99.2,
n = 205) may be an unsupported finding of the VPZ phase III study.
The eradication rate of CAM-­
S H. pylori-­
infected patients in our
prospective, multicenter cohort study was 88.9% (95% CI = 83.4%-­
93.1%, n = 180) in those treated with V-­AC regimen and 84.2% (95%
CI = 78.4-­89.1, n = 197) in those treated with PPI-­AC (P = .23).16 We
suggest that our present results are more significant than those of
the VPZ phase III trial; we treated patients in real clinical situations.
Secondly, we found that the efficacy of V-­
AC 7-­
day triple
therapy for CAM-­resistant H. pylori infections was grade D (poor;
81%-­84%); analogous PPI-­AC 7-­day triple therapy was graded as
unacceptable (<80%) in previous studies. We confirmed these find-
ings; we emphasize that the UBT should be performed no earlier
than 8 weeks after eradication therapy, thus not after only 4 weeks,
as in the phase III trial. We are of the view that VPZ may eradi-
cate CAM-­resistant H. pylori infections, consistent with the 70.2%
(95% CI = 53.0%-­84.1%, n = 37) eradication rate of V-­AC therapy
after failure of rabeprazole/AMPC/CAM.26 V-­AC treatment may be
adjusted in terms of dose, dosing interval, and treatment duration.
However, we suggest that the 7-­day regimen for CAM-­resistant
H. pylori is inappropriate, as this is a grade D approach. We are cur-
rently exploring the utilities of other regimens. The VPZ/AMPC/
MTZ 7-­day triple therapy regimen covered by the Japanese health
insurance system is a good option; MTZ resistance is negligible, and
the cure rate with this regimen is excellent.27
|
      7 of 8
In addition, we confirmed the V-­AC regimen to be safe. Thus,
higher drug doses over longer times may be possible. As expected,
we confirmed the data obtained in our prior prospective, multicenter
cohort comparison of V-­AC and PPI-­AC; VPZ-­based triple therapy was
safe and well-­tolerated.
The eradication rates of CAM-­resistant infections were greater
than those reported previously, whereas those of CAM-­susceptible
infections were not. The reason is unclear but may be attributable to
the rapid, long-­acting acid-­inhibitory effect of VPZ.28 It is very inter-
esting that we found no significant difference between second-­line
VPZ/AMPC/MTZ and PPI/AMPC/MTZ but a significant difference
between first-­line V-­AC and PPI-­AC. CAM and AMPC kill H. pylori
growing at a pH > 6. However, MTZ (which targets DNA) acts inde-
pendently of the growth phase. VPZ/CAM/MTZ therapy was better
than PPI/CAM/MTZ therapy.29 Together, the results suggest that
CAM and VPZ together target CAM-­resistant H. pylori.
Our study had certain limitations. First, this was not a double-­blind
trial. However, the UBT used to assess the primary outcome is ob-
jective, and the technicians were blinded to the treatment regimen
and the purpose of the research. Second, we did not evaluate the
CYP2C19 genotype. However, this is not important in terms of VPZ
action, as VPZ is metabolized principally by CYP3A4, which exhibits a
low level of polymorphism.
Antimicrobial susceptibility testing suggested that the 7-­day V-­AC
regimen was of grade C, as was the 7-­day PPI-­AC regimen, in patients
infected with CAM-­susceptible H. pylori. However, the eradication
rate of the V-­AC regimen in patients infected with CAM-­resistant
H. pylori was 82.9%, indicating that VPZ-­based regimens may be use-
ful. Our results suggest that the Japanese national insurance system
should cover V-­AC regimen with modified doses, dosing interval, and
treatment duration and that modified V-­AC may be valuable in coun-
tries with high rates of CAM-­resistant H. pylori infection.
ET HI C S S TAT EM ENT
All work was performed in accordance with the Declaration
of Helsinki and the “Ethical Guidelines for Medical and Health
Research Involving Human Subjects” (March 2005, Japanese
Ministry of Health, Labor, and Welfare). The trial was registered in
UMIN-­CTR in line with a recommendation of the ICMJE (identifier
UMIN000016337). The protocol was approved by the institutional
review boards of all study sites.
I NS T I T U T I O NAL R EVI EW B OAR D S TAT EM ENT
The study was reviewed and approved by the ethics committee/in-
stitutional review board of Yokohama City University Hospital, Japan
(no. B150401015).
C L I NI C AL T R I AL R EG I S T R AT I O N
This study is registered at [https://upload.umin.ac.jp/cgi-open-
bin/ctr_e/ctr_view.cgi?recptno=R000018957], with identification
 |
8 of 8       SUE et al.

number UMIN0000150401015. This trial registry [www.umin.ac.jp/ 15. Nishida T, Tsujii M, Tanimura H, et al. Comparative study of esomepra-
ctr/index/htm] is recognized by the ICMJE. zole and lansoprazole in triple therapy for eradication of Helicobacter
pylori in Japan. World J Gastroenterol. 2014;20:4362‐4369.
16. Sue S, Kuwashima H, Iwata Y, et al. The superiority of vonoprazan-­
based first-­ line triple therapy with clarithromycin: a prospective
IN FORME D CONSEN T S TATE M E N T
multi-­center cohort study on Helicobacter pylori eradication. Intern
All study participants provided written informed consent prior to Med. 2017;56:1277‐1285.
17. Villoria A, Garcia P, Calvet X, Gisbert JP, Vergara M. Meta-­analysis: high-­
study enrollment.
dose proton pump inhibitors vs. standard dose in triple therapy for
Helicobacter pylori eradication. Aliment Pharmacol Ther. 2008;28:868‐877.
18. Xiao L, Huang Q, Yank V, Ma J. An easily accessible Web-­based min-
D ISCLOSURE S OF I N TE RE S TS
imization random allocation system for clinical trials. J Med Internet
Res. 2013;15:e139.
None of the authors have any conflict of interests.
19. Dore MP, Leandro G, Realdi G, Sepulveda AR, Graham DY. Effect of
pretreatment antibiotic resistance to metronidazole and clarithromy-
cin on outcome of Helicobacter pylori therapy: a meta-­analytical ap-
O RCI D
proach. Dig Dis Sci. 2000;45:68‐76.
20. Noda H, Noguchi S, Yoshimine T, et al. A novel potassium-­competitive
Shin Maeda  http://orcid.org/0000-0002-0246-1594
acid blocker improves the efficacy of clarithromycin-­containing 7-­day
triple therapy against Helicobacter pylori. J Gastrointestin Liver Dis.
2016;25:283‐288.
REFERENCES 21. Matsumoto H, Shiotani A, Katsumata R, et al. Helicobacter pylori
eradication with proton pump inhibitors or potassium-­competitive
1. Lee YC, Chiang TH, Chou CK, et al. Association between Helicobacter
acid blockers: the effect of clarithromycin resistance. Dig Dis Sci.
pylori eradication and gastric cancer incidence: a systematic review
2016;61:3215‐3220.
and meta-­analysis. Gastroenterology. 2016;150:1113‐1124 e5.
22. Suzuki S, Gotoda T, Kusano C, Iwatsuka K, Moriyama M. The Efficacy
2. Herrero R, Park JY, Forman D. The fight against gastric cancer –
and tolerability of a triple therapy containing a potassium-­competitive
the IARC Working Group report. Best Pract Res Clin Gastroenterol.
acid blocker compared with a 7-­day PPI-­based low-­dose clarithromy-
2014;28:1107‐1114.
cin triple therapy. Am J Gastroenterol. 2016;111:949‐956.
3. Graham DY, Fischbach L. Helicobacter pylori treatment in the era of
23. Gisbert JP, Gonzalez L, Calvet X, et al. Proton pump inhibitor, clarithromy-
increasing antibiotic resistance. Gut. 2010;59:1143‐1153.
cin and either amoxycillin or nitroimidazole: a meta-­analysis of eradication
4. Megraud F, Coenen S, Versporten A, et al. Helicobacter pylori resis-
of Helicobacter pylori. Aliment Pharmacol Ther. 2000;14:1319‐1328.
tance to antibiotics in Europe and its relationship to antibiotic con-
24. Take S, Mizuno M, Ishiki K, et al. Interleukin-­1beta genetic polymor-
sumption. Gut. 2013;62:34‐42.
phism influences the effect of cytochrome P 2C19 genotype on the
5. Thung I, Aramin H, Vavinskaya V, et al. Review article: the global emer-
cure rate of 1-­week triple therapy for Helicobacter pylori infection. Am
gence of Helicobacter pylori antibiotic resistance. Aliment Pharmacol
J Gastroenterol. 2003;98:2403‐2408.
Ther. 2016;43:514‐533.
25. Kuwayama H, Asaka M, Sugiyama T, et al. Rabeprazole-­based erad-
6. Murakami K, Sakurai Y, Shiino M, Funao N, Nishimura A, Asaka M.
ication therapy for Helicobacter pylori: a large-­scale study in Japan.
Vonoprazan, a novel potassium-­competitive acid blocker, as a component
Aliment Pharmacol Ther. 2007;25:1105‐1113.
of first-­line and second-­line triple therapy for Helicobacter pylori eradica-
26. Inaba T, Iwamuro M, Toyokawa T, Okada H. Letter: promising re-
tion: a phase III, randomised, double-­blind study. Gut. 2016;65:1439‐1446.
sults of Helicobacter pylori eradication with vonoprazan-­based triple
7. Liou JM, Fang YJ, Chen CC, et al. Concomitant, bismuth qua-
therapy after failure of proton pump inhibitor-­based triple therapy.
druple, and 14-­ day triple therapy in the first-­ line treatment of
Aliment Pharmacol Ther. 2016;43:179‐180.
Helicobacter pylori: a multicentre, open-­label, randomised trial. Lancet.
27. Nishizawa T, Maekawa T, Watanabe N, et al. Clarithromycin versus
2016;388:2355‐2365.
metronidazole as first-­ line Helicobacter pylori eradication: a multi-
8. Tong YF, Lv J, Ying LY, et al. Seven-­day triple therapy is a better choice
center, prospective, randomized controlled study in Japan. J Clin
for Helicobacter pylori eradication in regions with low antibiotic resis-
Gastroenterol. 2015;49:468‐471.
tance. World J Gastroenterol. 2015;21:13073‐13079.
28. Sakurai Y, Mori Y, Okamoto H, et al. Acid-­inhibitory effects of vono-
9. Graham DY, Lu H, Yamaoka Y. A report card to grade Helicobacter py-
prazan 20 mg compared with esomeprazole 20 mg or rabeprazole
lori therapy. Helicobacter. 2007;12:275‐278.
10 mg in healthy adult male subjects–a randomised open-­label cross-­
10. Murakami K, Sakurai Y, Shiino M, Funao N, Nishimura A, Asaka M. Reply to
over study. Aliment Pharmacol Ther. 2015;42:719‐730.
the letter by Dr Graham concerning ethical and interpretation issues with
29. Ono S, Kato M, Nakagawa S, Mabe K, Sakamoto N. Vonoprazan im-
vonoprazan-­containing H. pylori eradication therapy. Gut. 2016;66:386.
proves the efficacy of Helicobacter pylori eradication therapy with a
11. Kawai T, Yamagishi T, Yagi K, et al. Tailored eradication therapy based
regimen consisting of clarithromycin and metronidazole in patients
on fecal Helicobacter pylori clarithromycin sensitivities. J Gastroenterol
allergic to penicillin. Helicobacter. 2017;22:e12374.
Hepatol. 2008;23(Suppl 2):S171‐S174.
12. Liou JM, Chen CC, Chen MJ, et al. Sequential versus triple therapy
for the first-­line treatment of Helicobacter pylori: a multicentre, open-­
label, randomised trial. Lancet. 2013;381:205‐213. How to cite this article: Sue S, Ogushi M, Arima I, et al.
13. Kirchheiner J, Glatt S, Fuhr U, et al. Relative potency of proton-­ Vonoprazan-­ vs proton-­pump inhibitor-­based first-­line 7-­day
pump inhibitors-­comparison of effects on intragastric pH. Eur J Clin
triple therapy for clarithromycin-­susceptible Helicobacter pylori:
Pharmacol. 2009;65:19‐31.
14. Inaba T, Mizuno M, Kawai K, et al. Randomized open trial for compar- A multicenter, prospective, randomized trial. Helicobacter.
ison of proton pump inhibitors in triple therapy for Helicobacter pylori 2017;e12456. https://doi.org/10.1111/hel.12456
infection in relation to CYP2C19 genotype. J Gastroenterol Hepatol.
2002;17:748‐753.