Research Article

Digestion Received: June 6, 2019

Accepted after revision: July 23, 2019
DOI: 10.1159/000502287 Published online: August 21, 2019

Dual Therapy with Vonoprazan and Amoxicillin Is

as Effective as Triple Therapy with Vonoprazan,
Amoxicillin and Clarithromycin for Eradication of
Helicobacter pylori
Takahisa Furuta a Mihoko Yamade b Takuma Kagami b Takahiro Uotani b
Takahiro Suzuki b Tomohiro Higuchi b Shinya Tani c Yasushi Hamaya b
Moriya Iwaizumi d Hiroaki Miyajima b Kazuo Umemura a, e Satoshi Osawa c
Ken Sugimoto b
a Center for Clinical Research, Hamamatsu University School of Medicine, Hamamatsu, Japan; b First Department

of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan; c Department of Endoscopic

and Photodynamic Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan; d Department
of Laboratory Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan; e Department of
Pharmacology, Hamamatsu University School of Medicine, Hamamatsu, Japan

Keywords
Helicobacter pylori · Eradication · Dual therapy · Vonoprazan
Abstract
Backgrounds/Aims: Vonoprazan (VPZ) is the first clinically
available potassium competitive acid blocker. This class of
agents provides faster and more potent acid inhibition than
proton pump inhibitors. Most strains of Helicobacter pylori
are sensitive to amoxicillin. We hypothesized that dual ther-
apy with VPZ and amoxicillin would provide the sufficient
eradication rate for H. pylori infection. To evaluate this, we
compared the eradication rate by the dual VPZ/amoxicillin
therapy with that by the standard triple VPZ/amoxicillin/
clarithromycin therapy. Methods: Non-inferiority of the
eradication rate of H. pylori by the dual therapy with VPZ
20 mg twice daily (bid) and amoxicillin 500 mg 3 times daily
(tid) for 1 week to that by the triple therapy with VPZ 20 mg
bid, amoxicillin 750 mg bid and clarithromycin 200 mg bid
for 1 week was retrospectively studied. Propensity score
matching was performed to improve comparability between
2 regimen groups. Successful eradication was diagnosed us-
ing the [13C]-urea breath test at 1–2 months after the end of
eradication therapy. Results: The intention-to-treat analysis
demonstrated that the eradication rate by the dual therapy
(92.9%; 95% CI 82.7–98.0%, 52/56) was not inferior to that of
the triple therapy (91.9%; 95% CI 80.4–97.0%, 51/56; OR
1.275, 95% CI 0.324–5.017%, p = 0.728). There were no statis-
tically significant differences in incidences of adverse events
between 2 regimens. Conclusion: VPZ-based dual therapy
(VPZ 20 mg bid and amoxicillin 500 mg tid for 1 week) pro-
vides an acceptable eradication rate of H. pylori infection
without the need for second antimicrobial agents, such as
clarithromycin. © 2019 S. Karger AG, Basel
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© 2019 S. Karger AG, Basel Takahisa Furuta, MD, PhD

Center for Clinical Research
Hamamatsu University School of Medicine
Göteborgs Universitet

E-Mail karger@karger.com
1-20-1, Handa-Yama, Higashi-Ku, Hamamatsu 431-3192 (Japan)
www.karger.com/dig
Downloaded by:

E-Mail furuta @ hama-med.ac.jp

 Introduction
Regimens for eradication of Helicobacter pylori infec-
tion consist of an acid inhibitor, such as a proton pump
inhibitor (PPI), and antimicrobial agents [1]. Acid inhib-
itors are necessary for antimicrobial agents to be more
stable and bioavailable in the stomach and for H. pylori
strains to be more sensitive to antimicrobial agents [2].
Therefore, the degree of acid inhibition is one of the im-
portant factors associated with the success or failure of
eradication therapy [3].
Vonoprazan (VPZ) is the first clinically available potas-
sium competitive acid blocker [4]. VPZ can attain the more
potent gastric acid inhibition in comparison with PPIs [5,
6]. The pH ≥4 and ≥5 holding-time ratios achieved by VPZ
20 mg twice daily (bid) on day 7 of the treatment were 100%
and 99%, respectively [5]. Moreover, VPZ can attain the
pH 7 in the stomach within around 3 h after the initial dos-
ing of 20 mg [6]. Therefore, when VPZ is used for the erad-
ication of H. pylori, it can make the ideal pH condition for
eradication of H. pylori in the stomach from day 1 of erad-
ication therapy, resulting that antimicrobial agents are ex-
pected to be bioavailable and stable and work fully in the
stomach from day 1. Then, VPZ has changed the eradica-
tion therapy dramatically in Japan. In the first clinical trial
performed in Japan, the eradication rate of H. pylori by the
VPZ containing triple therapy with amoxicillin and clar-
ithromycin was reported to be 92.6%, while that by the PPI
(e.g., lansoprazole) containing regimen was 75.9% [7].
Therefore, the recent most popular standard regimen for
eradication of H. pylori in Japan is now the triple regimen
with VPZ 20 mg bid, amoxicillin 750 mg bid and clarithro-
mycin 200 or 400 mg bid for 7 days [7], although regimens
used in the outside of Japan have been changed from the
triple therapy to non-bismuth or bismuth quadruple ther-
apies because PPI-based triple therapies can no longer at-
tain the sufficient eradication rates [8].
Interestingly, the eradication rate attained by the triple
regimen with VPZ 20 mg bid, amoxicillin 750 mg bid and
clarithromycin 200 or 400 mg bid for 7 days in patients
infected with clarithromycin-resistant strains of H. pylori
was 82% [7], which suggests that the dual therapy with
VPZ 20 mg bid and amoxicillin 750 mg bid for 1 week can
attain around 82% of eradication rate. However, 82% of
eradication rate is thought to be somewhat insufficient.
Amoxicillin is often involved in the regimens for eradi-
cation of H. pylori because the incidence of amoxicillin-
resistant strains of H. pylori is low in the treatment naïve
cases [9–11]. In most regimens, amoxicillin is dosed bid.
However, the bactericidal effect of amoxicillin depends on
2 Digestion
DOI: 10.1159/000502287
the per cent time above minimum inhibitory concentra-
tion (MIC) (%T > MIC), neither on maximum concentra-
tion/MIC nor on AUC (area under the plasma concentra-
tion time-curve)/MIC [12]. Because the plasma half-life of
amoxicillin is short [13], the bid dosing of amoxicillin ap-
pears theoretically inappropriate and 3 or 4 times daily
dosing (tid or qid) is reasonable for amoxicillin to make the
%T > MIC longer [14]. As a matter of fact, the regimens
with qid dosing of amoxicillin without 2nd antibiotic could
yield higher eradication rates in patients refractory to the
usual standard regimens [15–18], whereas the bid dosing
of amoxicillin could not attain sufficient eradication rates,
even though a higher dose of a PPI and amoxicillin were
used (i.e., the eradication rate by rabeprazole (RPZ) 20 mg
bid and amoxicillin 1,000 mg bid for 14 days was 59%) [19].
We previously reported that dual therapy with a PPI and
tid or qid dosing of amoxicillin 500 mg attained sufficient
eradication rates of H. pylori in poor metabolizer genotypes
of cytochrome P450 2C19 (CYP2C19) [20, 21] and that the
sufficient eradication rate was attained by the dual therapy
with higher doses of PPI (e.g., RPZ 10 mg qid) and amoxi-
cillin 500 mg qid [15, 22], which suggests that when gastric
acid secretion is potently inhibited, the dual therapy with a
potent acid inhibitor and amoxicillin dosed tid or qid can
attain the sufficient eradication of H. pylori. Because the
acid inhibitions attained by the bid dosing of VPZ 20 mg in
rapid, intermediate and poor metabolizers of CYP2C19
were all greater than that attained by the esomeprazole
20 mg bid in the poor metabolizers of CYP2C19 [5], the dual
therapy with VPZ 20 mg bid and amoxicillin dosed in tid or
qid manners is theoretically expected to attain the sufficient
eradication rates as observed in the previous studies [15].
Clarithromycin has often been involved in the stan-
dard eradication regimens. However, because clarithro-
mycin is a well-known potent inhibitor of cytochrome
P450 3A4 (CYP3A4) and P-glycoprotein (p-Gp), there
are risks of adverse events related to the drug-drug inter-
action between clarithromycin and substrates of CYP3A4
and p-Gp, such as lovastatin [23], triazolam [24] and cy-
closporine [25]. Moreover, clarithromycin has the risk of
arrhythmia [26]. Then, in our hospital, we have used the
dual therapy with VPZ and amoxicillin as the clarithro-
mycin-free regimens and experienced the high eradica-
tion rates of H. pylori infection.
Based on the backgrounds noted above, we examined
the efficacy of the dual therapy with VPZ 20 mg bid and
amoxicillin 500 mg tid for 1 week in comparison with the
standard triple regimen in Japan, consisting of VPZ
20 mg bid, amoxicillin 750 mg bid and clarithromycin
200 mg bid for 1 week.
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 Methods
Study Design and Oversight
This was a retrospective study and compared the efficacy and
safety of dual therapy with VPZ and amoxicillin with those of the
triple therapy with VPZ, amoxicillin and clarithromycin for the
eradication of H. pylori. The primary end point was the eradication
rate. The secondary end point included safety.
The study was designed by the first author in collaboration with
the other investigators. The protocol was approved in advance by
the Ethics Committee of Hamamatsu University School of Medi-
cine (15-006).
All authors vouch for the accuracy of the data and analyses and
for the fidelity of this report to the protocol. The draft of the man-
uscript was written by the first author and revised by a medical
writer (G.H.). Subsequent drafts were revised and reviewed by all
the authors. All the authors made the decision to submit the man-
uscript for publication. All authors contributed to the manuscript.
Patients
A total of 709 patients who visited to the H. pylori-specific out-
patient unit of the hospital of Hamamatsu University School of
Medicine (1-20-1, Handayama, Higashiku, Hamamatsu, 431-
3192, Japan) from March 2015 to 2019 were screened from the
medical records. Written informed consents were obtained from
all of them for the use of their treatment results for medical re-
search at the first visit to the hospital. We did not perform the
eradication therapy to patients with severe general condition, such
as renal insufficiency or liver dysfunction, inability to undergo
eradication therapy and serious complications considered to pre-
vent completion of the study.
All patients underwent the gastroduodenoscopy for the careful
investigation of the oesophagus, stomach and duodenum and for
the examination of the status of H. pylori infection after the written
informed consents for esophago-gastro-duodenoscopy were ob-
tained. H. pylori infection was confirmed by rapid urease test (He-
lico Check, Otsuka Pharmaeutical Co., Ltd., Tokyo, Japan). Gastric
atrophy was assessed based on Kyoto classification of gastritis and
classified into the closed type and open type [27].
Eligible patients were treated with the dual therapy, the triple
therapy or other regimens, such as tailored therapies. Patients in
the dual therapy group were treated with VPZ 20 mg bid and
amoxicillin 500 mg tid for 1 week. Those in the triple therapy
group were treated with VPZ 20 mg bid, amoxicillin 750 mg bid
and clarithromycin 200 mg bid for 1 week. Probiotics (Bio
Three® 6 tables/day, Toa Shinyaku Co., Ltd., Tokyo, Japan) was
also prescribed to all patients for 7 days of the eradication thera-
py.
At 1–2 months after the end of each of eradication regimens,
patients underwent the [13C]-urea breath test as previously de-
scribed for the judgment of success or failure of eradication [28].
Adverse events during the period of eradication therapy were as-
sessed by medical records of the interview on the day of the [13C]-
urea breath test.
Sample Size Estimation
The aim of the study was to verify the non-inferiority of the
dual VPZ/amoxicillin therapy to the triple VPZ/amoxicillin/clar-
ithromycin therapy as the first-line therapy for the eradication of
H. pylori. The eradication rate by the triple therapy with VPZ
Dual VPZ/Amoxicillin Therapy for
H. pylori Infection
20 mg bid, amoxicillin 750 mg bid and clarithromycin 200 mg bid
was repoeradication92.6% [7]. In this study, the eradication rate in
the group infected with clarithromycin resistant strain was 82%,
suggesting that the eradication rate by the dual therapy with VPZ
20 mg bid and amoxicillin 750 mg bid was around 82%. In our
previous study, the change of the dosing scheme of amoxicillin
from 750 mg bid to 500 mg tid increased the eradication rate from
77.8 to 93.5% (15.7% up) in the PPI-based regimens [14]. There-
fore, around 95% of the eradication rate was expected to be
achieved by the dual therapy with VPZ 20 mg bid and amoxicillin
500 mg tid for 1 week. Under these eradication rates, when the
non-inferior margin was set to be 0.1, α was set to be 0.05 and 1-β
was set to be 0.8, the appropriate sample size was calculated as 47
per each group.
Propensity Score Matching
To compare the eradication rate of the dual VPZ/amoxicillin
therapy with that of the triple VPZ/amoxicillin/clarithromycin
therapy, patients treated with the dual therapy and those with the
triple therapy as the first-line therapy for the eradication of H. py-
lori were selected from the medical records. To minimize the po-
tential confounding and selection bias, we used the propensity
score matching to identify the controls treated with triple therapy.
Age, sex and gastric atrophy graded by Kyoto classification of gas-
tritis were used as the matching scores, because these parameters
were related to the eradication rates of H. pylori [29]. Selection of
cases and controls from our medical records by the propensity
score matching was performed by the SPSS (IBM® SPSS® Statistics
version 23).
Statistics
The non-inferiority of dual therapy to the triple therapy was
evaluated for the primary end point using the Farrington and
Manning test [30] with a non-inferiority margin of 10%. Statistical
differences in eradication rates as a post hoc analysis and incidenc-
es of adverse events between the 2 regimen groups were assessed
by chi square test. Numerical data were expressed as means ± SD.
Statistical differences in numerical data between the 2 regimen
groups were assessed by student t test. All statistical calculations
were performed using SPSS. p values <0.05 were considered statis-
tically significant.
Results
From March 2015 to 2019, a total of 709 patients vis-
ited the H. pylori-specific outpatient unit of our hospital
and were screened. Of them, a total of 62 patients were
treated with the dual therapy with VPZ 20 mg bid and
amoxicillin 500 mg tid for 1 week and 124 were treated
with the triple therapy with VPZ 20 mg bid, clarithromy-
cin 200 mg bid and amoxicillin 750 mg bid for 1 week as
the first-line therapy. Clinical characteristics of these pa-
tients are summarized in Table 1. Of 62 patients treated
with dual therapy, 58 succeeded in the eradication (93.5%,
95% CI 84.3–98.2%). Of the 124 patients treated with the
triple therapy, 112 could clear the infection (90.3%, 95%
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DOI: 10.1159/000502287
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 Assessed for eligibility
(n = 709)

Excluded (n = 523)
• Not meeting criteria (n = 493)
• Declined to participate (n = 30)

Dual VPZ/AMPC therapy Triple VPZ.AMPC/CAM therapy

(n = 62) (n = 124)

Popensity score matching

age, sex, gastric atrophy

Dual therapy group Triple therapy group

ITT analysis
(n = 56) (n = 56)

Lost to follow-up (n = 0) Lost to follow-up (n = 1)

Discontinued the therapy (n = 2) Discontinued the therapy (n = 0)

Fig. 1. Flow diagram of patients enrolled to

the study. VPZ, vonoprazan; AMPC, Analyzed (n = 54) PP analysis Analyzed (n = 55)
amoxicillin; CAM, clarithromycin; ITT,
intention to treat; PP, per protocol.

Table 1. Demographic clinical characteristics of patients treated Table 2. Demographic clinical characteristics of propensity score
with the dual or triple therapy matched patients treated with the dual or triple therapy

Dual Triple p value Dual Triple p value

therapy therapy therapy therapy
(n = 62) (n = 124) (n = 56) (n = 56)

Age, years, mean ± SD 60.2±12.2 62.5±3.0 0.254 Age, years, mean ± SD 60.8±12.3 60.7±12.1 0.963
Gender, male/female, n/n 33/29 69/55 0.755 Gender, male/female, n/n 30/26 30/26 1.000
Gastric atrophy: Gastric atrophy:
closed type/open type 24/38 48/75 0.921 closed type/open type 23/33 23/33 1.000
Gastritis only/peptic Gastritis only/peptic
ulcer/others, n/n/n 53/6/3 98/11/13 0.686 ulcer/others, n/n/n 47/6/3 46/5/4 0.831
Smoking habit, n 11 16 0.377 Smoking habit, n 10 8 0.607

CI 83.7–94.9%). There was no statistically significant
­difference in the eradication rates between the 2 regimens
(p = 0.552).
From them, 56 patients treated by the dual therapy
and 56 patients treated by the triple therapy were select-
ed by the propensity score matching (Fig. 1). Demo-
graphic clinical characteristics of patients with different
regimens groups were summarized in Table 2. There
were no statistically significant differences in the back-
grounds of patients between the 2 different regimen
groups.
Of 112 patients, 111 underwent [13C]-urea breath test
after eradication therapy. One patient in the triple thera-
py group did not undergo the [13C]-urea breath test. Two
patients in the dual therapy discontinued the treatment
because of the allergic reaction.
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DOI: 10.1159/000502287
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 sults indicated that the eradication rate by the dual therapy
Dual therapy Triple therapy
100
was not inferior to that by the triple therapy.
Two patients in the dual therapy group experienced
90 skin rush. They underwent the drug lymphocyte stimula-
80 tion test for amoxicillin and VPZ and found to be allergic
to amoxicillin. Other mild adverse events were observed

94.4% (95% CI 84.6–98.8%, 51/54)

92.9% (95% CI 82.7–98.0%, 52/56)

92.7% (95% CI 82.4–98.0%, 51/55)

70 91.9% (95% CI 80.4–97.0%, 51/56) as summarized in Table 3. There were no statistically sig-
Eradication rate, %

60 nificant differences in the incidences in the adverse events

between 2 regimens. The incidence of diarrhoea appeared
50 higher in the triple therapy group but that also was not
40 statistically significant.

30

20 Discussion

10 In the present study, the dual therapy with VPZ 20 mg

0 bid and amoxicillin 500 mg tid could attain the sufficient
ITT PP eradication rate (≥90%), which was identical to that by
the triple therapy with VPZ 20 mg bid + clarithromycin
Fig. 2. ITT and PP analyses of eradication rates attained by the dual 200 mg + amoxicillin 750 mg bid for 1 week, the current
therapy with VPZ and amoxicillin and the triple therapy with VPZ, standard first line regimen in Japan [7]. The study result
amoxicillin and clarithromycin. There were no statistically signif- suggests that the potent acid inhibition attained by the
icant differences in the eradication rates between 2 regimens. ITT, VPZ 20 mg bid can eradicate H. pylori with tid dosing of
intention to treat; PP, per protocol. amoxicillin without second antimicrobial agents, such as
clarithromycin or metronidazole.
Because of the increasing incidence of clarithromycin
Table 3. Incidences of adverse events observed in the dual or triple
therapy groups
resistant strains of H. pylori, the eradication rates attained
by the triple PPI/amoxicillin/clarithromycin therapy have
Dual therapy Triple therapy p value becoming decreased [31]. Then, the recent trends of erad-
(n = 56) (n = 56) ication regimens have been changed from the triple regi-
mens to other appropriate regimens, such as bismuth or
Skin rush, n 2 0 0.154
Diarrohea, n 5 10 0.165
non-bismuth quadruple therapies, such as sequential and
Constipation, n 1 0 0.315 concomitant therapies [8]. The eradication rates attained
Abdominal pains, n 1 2 0.558 by the concomitant therapy have been reported to be high-
Nausea, n 0 1 0.315 er than 90%. However, this regimen consists of 3 antimi-
Dysgeusia, n 0 1 0.315 crobial agents (i.e., The eradication rate by amoxicillin
1,000 mg bid, metronidazole or imidazole 500 mg bid and
clarithromycin 500 mg bid and PPIs dosed for 14 days was
91.7% [32]). On the other hand, the VPZ-based triple ther-
The intention to treat analyses of the eradication rates apy for 1 week (VPZ 20 mg bid, clarithromycin 200 or
of dual therapy and triple therapy were the 92.9% (95% CI 400 mg and amoxicillin 750 mg bid) attained the 92.6% of
82.7–98.0%, 52/56) and 91.9% (95% CI 80.4–97.0%, 51/56), eradication rate [7]; then, this triple regimen has settled as
respectively (p = 0.728). Those by the per-protocol analyses the most popular first-line regimen in Japan. Interestingly,
were 94.4% (95% CI 84.6–98.8%, 51/54) and 92.7% (95% the eradication rate attained by the triple therapy with
CI 82.40–98.0%, 51/55) respectively (p = 0.715; Fig. 2). The VPZ in patients infected with clarithromycin-resistant
lower limit (82.7%) of the eradication rate of the dual ther- strains of H. pylori was 82% [7], suggesting that dual regi-
apy was higher than the non-inferiority margin (95% CI men with VPZ 20 mg bid and amoxicillin 750 mg bid could
91.9–10%, p = 81.9%) of the triple therapy. The OR of the attain the eradication rate of around 80% as noted above.
eradication rate of the dual therapy to that of the triple ther- There have been several reports on the dual therapy
apy was 1.275 (95% CI 0.324–5.017, p = 0.728). These re- with PPIs and amoxicillin. The representative reports are
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Dual VPZ/Amoxicillin Therapy for Digestion 5

H. pylori Infection DOI: 10.1159/000502287
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Table 4. Reports on the eradication of Helicobacter pylori by the dual therapy with amoxicillin and PPIs

First author Year Dosing scheme Dosing scheme of PPI Duration of Number Eradication
of amoxicillin treatment, days rate (%; ITT)

Furuta [16] 2001 500 RPZ 10 mg qid 14 17 100.0

Tai [33] 2019 750 mg qid EPZ 40 mg tid 14 120 91.7
Shirai [34] 2007 500 mg qid RPZ 10 mg qid 14 66 90.9
Furuta [15] 2010 500 mg qid RPZ 10 mg qid 14 49 87.8
Miehlke [17] 2003 750 mg qid OPZ 40 mg qid 14 38 83.8
Furuta [21] 2001 500 mg tid RPZ 10 mg bid 14 97 81.4
Schwartz [35] 1998 1,000 mg tid LPZ 30 mg tid 14 51 77
Miehlke [36] 2006 1,000 mg tid OPZ 40 mg tid 14 72 70
Miyoshi [37] 2001 500 mg tid OPZ 20 mg bid 14 98 66.3
Nishizawa [44] 2012 500 mg qid RPZ 10 mg qid 14 46 63.0
Miyoshi [37] 2001 500 mg tid RPZ 10 mg tid 14 101 62.4
Isomoto [19] 2003 1,000 mg bid RPZ 20 mg bid 14 63 59
Wong [38] 2000 1,000 mg bid LPZ 30 mg bid 14 75 57
Attumi [39] 2014 1,000 mg bid Dexlansoprazole 120 mg bid 14 13 53.8
Schwartz [35] 1998 1,000 mg tid LPZ 30 mg bid 14 49 3
Koizumi [40] 1998 500 mg tid OPZ 20 mg qd 14 25 52
Furuta [20] 1998 500 mg qid OPZ 20 mg qd 14 62 50
Bell [41] 1995 500 mg tid OPZ 40 mg qd 14 60 46
Cottrill [42] 1997 1,000 mg bid OPZ 40 mg qd 14 85 44
Kagaya [43] 2000 750 mg bid LPZ 30 mg qd 14 24 43

PPI, proton pump inhibitor; EPZ, esomeprazole; LPZ, lansoprazole; OPZ, omeprazole; RPZ, rabeprazole; qd, once daily; bid, twice
daily; tid, three times daily; qid, four-times daily.

listed in the orders of eradication rates in the Table 4 [15–
17, 19–21, 33–44]. As shown in Table 4, the reported erad-
ication rates attained by dual therapy with a PPI and amox-
icillin have varied. However, in the regimens that attained
the eradication rates higher than 80%, amoxicillin was
dosed 3 times (tid) or 4 times (qid) daily and PPI was dosed
qid except one report. Shirai et al. [34] reported that the
intention to treat and per-protocol analyses of eradication
rate attained by the dual therapy with RPZ 10 mg qid +
amoxicillin 500 mg qid for 14 days were 90.9 and 93.8%
respectively. In our previous study where amoxicillin
500 mg was dosed tid, the sufficient eradication rate was
achieved with the bid dosing of RPZ 10 mg in intermediate
(91.7%) and poor (93.8%) metabolizers of CYP2C19 [21].
On the other hand, all regimens where amoxicillin was
dosed bid could not attain the sufficient eradication rates
(<60%), suggesting that at least tid dosing of amoxicillin
500 mg under the sufficient acid inhibition is necessary to
attain the sufficient eradication rates of H. pylori.
In the present study, the period of the eradication was
set to be 1 week because of the following reasons. First,
the intragastric pH reaches around 7 within 3–4 h after
the first dosing of VPZ 20 mg [6]. Second, the eradication
rate attained by the 1-week VPZ-based triple therapy was
82% in patients infected with clarithromycin-resistant
strains of H. pylori. Usually, amoxicillin-sensitive strains
of H. pylori cannot survive for 1 week on the agar plates
containing amoxicillin at pH 7. Therefore, the 1-week was
thought to be enough for amoxicillin to work well if the
sufficient pH condition was provided in the stomach.
Whether the further longer treatment period can attain
the further higher eradication rate should be verified by
the appropriated clinical study.
There are several merits in the regimen without clar-
ithromycin, which can be proved by the following rea-
sons. First, because clarithromycin is a well-known inhib-
itor of p-Gp and CYP3A4 [45, 46], the interaction be-
tween clarithromycin and substrates of P-Gp and CYP3A4
is a cause for concern; clarithromycin increases plasma
levels of the substrates of CYP3A4 and MDR1, such as
statins, cyclosporine, calcium receptor antagonists, car-
bamazepine, and so on. Therefore, a careful attention is
necessary for patients on the concomitant medicines [47].
Second, clarithromycin is known to have the risk of elon-
gation of QT interval [48]. Therefore, there is a risk of sud-
den death by arrhythmia in the use of clarithromycin [49].
Third, macrolide antibiotics are known to stimulate the
intestinal peristalsis [50], which is related to the increased
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incidence of diarrhoea during the eradication treatment.
In the present study, the incidence of diarrhoea appeared
higher in the triple therapy group. Anyway, although se-
vere adverse events associated with clarithromycin were
not observed in the present study, clinicians must know
that clarithromycin has the potentials of these risks.
Finally, our study results must be interpreted within
the study limitations, which are as follows: First, this is the
retrospective study, although propensity score marching
was used for the selection of patients. Second, this is a
single-centre study, not a multicentre study. Last, we did
not test the effect of qid dosing of amoxicillin. Therefore,
whether qid dosing could attain the higher eradication
rate in comparison with tid dosing is unclear. Therefore,
a further study is needed to verify the results of the pres-
ent study by the appropriate prospective multicentre
study design including sufficient number of patients.
In conclusion, we demonstrated that the dual therapy
with VPZ 20 mg plus amoxicillin 500 mg tid could attain
the sufficient eradication rate of H. pylori without second
antimicrobial agents such as clarithromycin and metro-
nidazole. The present study result indicates that eradica-
tion of H. pylori can be attained by selecting one suscep-
tible antimicrobial agent and dosing it with the appropri-
ate dosing schemes (i.e., tid for amoxicillin) under the
sufficient acid inhibition. This sufficient acid inhibition
cannot be accomplished by PPIs but can be accomplished
with VPZ. Therefore, VPZ will change the concept of de-
sign of eradication regimens soon.
Acknowledgments
We greatly appreciate the help of the staff of the endoscopy
unit, namely, Ms. Hiroko Iwata, Ms. Yoko Suzuki, Ms. Junko
Ishiduka, Ms. Azusa Umeda, Ms. Naoko Kamiya, Ms. Rieko
Kawai, Ms. Noriko Kawakami, Ms. Chiaki Kawaguchi, Ms. To-
moko Kumagai, Ms. Yumie Suganuma, Ms. Mari Suzuki, Ms. No-
bue Takahashi, Ms. Naoko Fujimoto, Ms. Chieko Matsumoto, Ms.
Hisako Murase, Ms. Natsumi Ikuma, Ms. Keiko Kikuchi, Ms.
Chikako Sasagase, Ms. Mieko Suzuki, Ms. Satoko Takebayashi,
Ms. Emiko Tomatsu, Ms. Kinuko Maruyama, and Ms. Atsumi
Murai.
Statement of Ethics
The protocol was approved in advance by the Ethics Commit-
tee of Hamamatsu University School of Medicine (15-006) as de-
scribed in the “Methods” section. Written informed consents were
obtained from all of them for the use of their treatment results for
medical research at their first visit to our hospital.
Disclosure Statement
None of authors have any conflict of interest related to the
study.
Funding Sources
The study was performed with the help of self-funding.
Author Contributions
T.F.: plan of the study, patient care, endoscopy of patients, sta-
tistical analysis and interpretation of the data and drafting of the
manuscript. M.Y. and T.U.: plan of the study, patient care, endos-
copy of patients and checking the manuscript. T.K.: plan of the
study, endoscopy of patients and checking the manuscript. T.S.:
endoscopy of patients and checking the manuscript. Y.H.: endos-
copy of patients. M.I.: patient care. S.O. and K.S.: patient care, en-
doscopy of patients and checking the manuscript. H.M. and K.U.:
patient care and checking the manuscript.

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