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ORiginal Article
Gut and Liver, Vol. 10, No. 4, July 2016, pp. 520-525
Effects of N-acetylcysteine on First-Line Sequential Therapy for
Helicobacter
pylori
Infection: A Randomized Controlled Pilot Trial
Hyuk Yoon1, Dong Ho Lee1,2, Eun Sun Jang1, Jaihwan Kim1, Cheol Min Shin1, Young Soo Park1, Jin-Hyeok Hwang1,
Jin-Wook Kim1, Sook-Hayng Jeong1, and Nayoung Kim1,2
1
Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, and
2
Department of Internal Medicine and Liver
Research Institute, Seoul National University College of Medicine, Seoul, Korea
Correspondence to: Dong Ho Lee
Department of Internal Medicine, Seoul National University Bundang Hospital, 82 Gumi-ro 173beon-gil, Bundang-gu, Seongnam 463-707, Korea
Tel: +82-31-787-7006, Fax: +82-31-787-4051, E-mail: dhljohn@yahoo.co.kr
Received on January 27, 2015. Revised on March 29, 2015. Accepted on April 10, 2015. Published online September 9, 2015
pISSN 1976-2283 eISSN 2005-1212 http://dx.doi.org/10.5009/gnl15048
Background/Aims: To evaluate the adjuvant effects of N-
acetylcysteine (NAC) on first-line sequential therapy (SQT) for
Helicobacter pylori
infection. Methods: Patients with
H. pylori
infections were randomly assigned to receive sequential
therapy with (SQT+NAC group, n=49) or without (SQT-only
group, n=50) NAC. Sequential therapy consisted of rabepra-
zole 20 mg and amoxicillin 1 g for the first 5 days, followed
by rabeprazole 20 mg, clarithromycin 500 mg and metro-
nidazole 500 mg for the remaining 5 days; all drugs were
administered twice daily. For the SQT+NAC group, NAC 400
mg bid was added for the first 5 days of sequential therapy.
H.
pylori
eradication was evaluated 4 weeks after the comple-
tion of therapy. Results: The eradication rates by intention-to-
treat analysis were 58.0% in the SQT-only group and 67.3%
in the SQT+NAC group (p=0.336). The eradication rates
by per-protocol analysis were 70.0% in the SQT-only group
and 80.5% in the SQT+NAC group (p=0.274). Compliance
was very good in both groups (SQT only/SQT+NAC groups:
95.2%/100%, p=0.494). There was no significant differ-
ence in the adverse event rates between groups (SQT-only/
SQT+NAC groups: 26.2%/26.8%, p=0.947). Conclusions:
The
H. pylori
eradication rate was numerically higher in the
SQT+NAC group than in the SQT-only group. As our data did
not reach statistical significance, larger trials are warranted.
(Gut Liver, 2016;10:520-525)
Key Words: Eradication;
Helicobacter pylori
; N-acetylcysteine;
Sequential therapy
INTRODUCTION
Standard triple therapy consisting of proton pump inhibitors
(PPIs), amoxicillin, and clarithromycin, has long been recom-
mended as first-line therapy for
Helicobacter pylori
infection.1,2
However, the eradication rate of this triple therapy has been
decreasing because of increasing antibiotic resistance;3,4 in fact,
it is now reported to be <80%.5 Sequential therapy is one of the
promising alternative regimens to standard triple therapy. Early
meta-analyses reported that the eradication rate of sequential
therapy is >90%.6-8 Therefore, this regimen is currently recom-
mended as the alternative first-line treatment for
H. pylori
infec-
tion by European guidelines.9 However, a recent meta-analysis
concluded that although this regimen appears to be superior to
standard triple therapy for
H. pylori
infection in Asian adults,
its pooled efficacy is lower than what was reported in earlier
European studies.10 Therefore, it remains controversial whether
sequential therapy (SQT) could replace standard triple therapy in
Asia.
Adjuvant agents to the eradication regimen have been con-
tinuously studied to improve the efficacy of
H. pylori
eradica-
tion therapy.11 One of these adjuvants consists of a material
that destroys biofilm since several studied demonstrated that
H.
pylori
forms biofilm that likely helps it survive on the gastric
mucosa epithelium.12,13 Among several candidates for antibio-
film therapeutic agents, N-acetylcysteine (NAC) has received
attention.5 NAC, a compound that has mucolytic and antioxi-
dant functions, has been widely used for respiratory and oto-
laryngologic diseases. In a mouse model, NAC was reported to
inhibit the growth of
H. pylori
,14 while the addition of NAC to
amoxicillin showed comparable eradication rates to standard
triple therapy.15 A Turkish study in humans suggested that the
addition of NAC could increase the eradication rate of dual
therapy consisting of a PPI and clarithromycin.16 In addition, a
resent Italian study demonstrated that NAC pretreatment before
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Yoon H, et al: N-acetylcysteine and
H. pylori
Eradication 521
a culture-guided antibiotic regimen is effective for overcoming
H.
pylori
antibiotic resistance in patients with a history of multiple
eradication failure.17
The key theoretical basis of sequential therapy is the effect
of amoxicillin on the bacterial cell wall. Amoxicillin, which
is administrated in the first half of the regimen, damages the
H. pylori
cell wall to overcome the antibiotic resistance and
increase the eradication rate by two mechanisms. First, the in-
jured cell wall could help the other antibiotics penetrate the
H.
pylori
strain. Second,
H. pylori
with damaged cell walls cannot
develop an efflux channel for clarithromycin.18,19 Therefore,
we hypothesized that the addition of NAC to the first half of
sequential therapy could increase the eradication rate by de-
stroying the biofilm and weakening the cell wall together with
amoxicillin. To test this hypothesis, we performed a randomized
open-labeled pilot study comparing the eradication rates of
H.
pylori
using sequential therapy with and without NAC.
MATERIALS AND METHODS
1. Patients
Between July 2013 and January 2014, patients with
H. pylori
infection were enrolled in this randomized open-labeled pilot
study at Seoul National University Bundang Hospital in South
Korea.
H. pylori
infection was defined based on the results of
at least one of the following three tests: (1) a positive 13C-urea
breath test (UBT) results; (2) histological evidence of
H. pylori
in the stomach by modified Giemsa staining; and (3) a positive
rapid urease test (CLO test; Delta West, Bentley, Australia) result
by gastric mucosal biopsy. Because there was a report that NAC
administration induced gastric ulcers in rats, patients with active
peptic ulcer disease were excluded.20 Patients with a history of
the use of PPIs, histamine-2 receptor antagonists, or antibiotics
within the previous 2 months were also excluded. All patients
were provided informed consent and this study was approved
by the Institutional Review Board of Seoul National University
Bundang Hospital (IRB number: B-1304/198-005).
2. Study design
Patients were randomly assigned to the SQT-only or SQT+NAC
group using a computer-generated table in blocks of four. The
SQT-only group received 10-day sequential therapy (rabeprazole
20 mg and amoxicillin 1 g for the first 5 days, followed by ra-
beprazole 20 mg, clarithromycin 500 mg and metronidazole 500
mg for the remaining 5 days; all drugs were administrated twice
daily). For the SQT+NAC group, NAC 400 mg bid was added for
the first 5 days of sequential therapy. Patients were instructed
not to take antibiotics for at least 4 weeks and PPIs for at least
2 weeks before testing for
H. pylori
infection to minimize the
chance of false negative results.
Four weeks after the completion of eradication therapy,
H.
pylori
infection was assessed by UBT. However, modified Giem-
sa staining and the rapid urease test were performed in patients
with gastric ulcer or gastric neoplasia for whom a follow-up
endoscopic examination was necessary. At this time, compli-
ance was evaluated by direct questioning and patients were
interviewed for adverse events. Noncompliance was defined as
drug intake <85%. Because smoking is known to increase the
treatment failure rate for
H. pylori
eradication,21 smoking his-
tory was also evaluated.
3. 13C-urea breath test
After a 4-hour fasting, each patient was administrated 100
mg of 13C-urea powder (UBiTkitTM; Otsuka Pharmaceutical Co.,
Ltd., Tokyo, Japan) dissolved in 100 mL of water. A second
breath sample was collected 20 minutes later. The samples were
analyzed using an isotope-selective nondispersive infrared spec-
trometer (UBiT-IR300Ⓡ; Otsuka Pharmaceutical Co., Ltd.). The
cutoff value for
H. pylori
eradication was 2.5‰.
4. Statistical analysis
Eradication rates of
H. pylori
were determined on intention-
to-treat (ITT) and per-protocol (PP) bases. All enrolled patients
were included in the ITT analysis. Patients who were lost to
follow-up, were noncompliant, or dropped out due to adverse
events were excluded from the PP analysis.
SPSS for Windows version 18.0 (SPSS Inc., Chicago, IL, USA)
was used for the statistical analyses. Continuous variables were
analyzed using Student t-test and categorical variables were as-
sessed using the chi-square test or Fisher exact test. All results
were considered to indicate statistical significance when the p-
values were <0.05. The statistical methods of this study were
reviewed by Medical Research Collaborating Center at Seoul
National University Bundang Hospital.
RESULTS
1. Patients’ clinical characteristics
Fig. 1 shows a schematic diagram of this study. One hundred
patients with
H. pylori
infection consented to participate in this
study and were randomly allocated to the SQT-only group or
the SQT+NAC group in a 1:1 ratio; one patient in the SQT+NAC
group withdrew consent. As a result, a total of 99 patients were
enrolled in this study (SQT-only group: 50 patients; SQT+NAC
group: 49 patients). There was no significant difference in base-
line demographics between the two groups (Table 1). About half
of the patients were diagnosed with nonulcer dyspepsia in both
groups.
H. pylori
infection was diagnosed by both histology and
rapid urease test in 75.6% (75/99) of patients. In the remaining
patients, a single method among histology, rapid urease test,
and UBT was used for the detection of
H. pylori
.
2.
H. pylori
eradication rates
Table 2 shows eradication rates of
H. pylori
in both groups.
522 Gut and Liver, Vol. 10, No. 4, July 2016
The eradication rates by ITT analysis were 58.0% (95% con-
fidence interval [CI], 43.8 to 72.2) and 67.3% (95% CI, 53.7
to 81.0) in the SQT-only and SQT+NAC groups, respectively
(p=0.336). The eradication rates by PP analysis after the ex-
clusion of 16 patients who were lost to follow-up and two
noncompliant patients were 70.0% (95% CI, 55.2 to 84.8) and
80.5% (95% CI, 67.8 to 93.2) in the SQT-only and SQT+NAC
groups, respectively (p=0.274). We additionally compared the
eradication rates of both groups divided by peptic ulcer disease
and nonulcer dyspepsia (Table 3). However, there was still no
significant difference in the ITT and PP eradication rates be-
tween two groups.
3. Compliance and adverse events
Compliance was very good in both groups (SQT-only group,
95.2%; SQT+NAC group, 100%; p=0.494). The adverse event
rates were 26.2% and 26.8% in the SQT-only and SQT+NAC
groups, respectively (p=0.947) (Table 4). The most common ad-
verse event was epigastric soreness in the SQT-only group and
diarrhea in the SQT+NAC group. No patient in either group dis-
continued eradication therapy because of adverse events. Two
patients in the SQT-only group complained of more than one
kind of adverse events. One of the two, a 41-year-old woman
visited the emergency room in the last half of the eradication
therapy because of severe adverse events. She complained of
diarrhea, a metallic taste, and dizziness. However, because there
were no abnormal laboratory findings, she was discharged with
100 Patients with infectionH. pylori
41 Patients
PP analysis
ITT analysis
50 Patients in the SQT-only group
8 F/U loss
2 Noncompliance
1 Withdrawal of consent
Random allocation by 1:1
50 Patients in the SQT-only group 50 Patients in the SQT+NAC group
49 Patients in the SQT+NAC group
40 Patients
8 F/U loss
0 Noncompliance
Fig. 1. Flow schematic of the study
included intention-to-treat and per-
protocol analyses.
H. pylori,
Helicobacter pylori
; SQT-only,
sequential therapy only; SQT+NAC,
sequential therapy+N-acetylcysteine;
ITT, intention-to-treat; F/U, follow-
up; PP, per-protocol.
Table 1. Clinical Characteristics of the Patients
Characteristic SQT-only
(n=50)
SQT+NAC
(n=49) p-value
Male sex 23 (46.0) 25 (51.0) 0.617
Age, yr 58.8±12.7 57.2±11.1 0.529
Disease 0.067
Peptic ulcer disease 5 (10.0) 9 (18.4)
Gastric dysplasia or cancer 11 (22.0) 2 (4.1)
Family history of gastric cancer 2 (4.0) 3 (6.1)
Chronic atrophic gastritis 7 (14.0) 11 (22.4)
Nonulcer dyspepsia 25 (50.0) 24 (49.0)
Smoking 0.778
Yes 5 (11.4) 6 (13.3)
No 39 (88.6) 39 (86.7)
Drop out
Follow-up loss 8 (16.0) 8 (16.3)
Noncompliance 2 (4.0) 0
Discontinued therapy because
of adverse events
0 0
Data are presented as number (%) or mean±SD.
SQT-only, sequential therapy only; SQT+NAC, sequential therapy+N-
acetylcysteine.
Table 2.
Helicobacter pylori
Eradication rates
SQT-only
(n=50)
SQT+NAC
(n=49) p-value
ITT analysis
Eradication rate, % 58.0 (29/50) 67.3 (33/49) 0.336
95% CI 43.8–72.2 53.7–81.0
PP analysis
Eradication rate, % 70.0 (28/40) 80.5 (33/41) 0.274
95% CI 55.2–84.8 67.8–93.2
SQT-only, sequential therapy only; SQT+NAC, sequential therapy+N-
acetylcysteine; ITT, intention-to-treat; CI, confidence interval; PP,
per-protocol.
Yoon H, et al: N-acetylcysteine and
H. pylori
Eradication 523
symptomatic medication and completed the remaining eradica-
tion regimen.
DISCUSSION
To our knowledge, this is the first study to evaluate the ad-
juvant effect of NAC on sequential therapy for
H. pylori
infec-
tion. We hypothesized that the addition of NAC, a mucolytic
agent, to sequential therapy would increase the eradication rate
by decreasing the viscosity of the gastric mucus and destroy-
ing the biofilm formed by
H. pylori
. The results showed that the
eradication rate in the SQT+NAC group was approximately 10%
higher than the eradication rate in the SQT-only group on the
ITT and PP analyses. However, these features did not reach sta-
tistical significance. A similar phenomenon was reported in the
recent Italian study.22 Although Karbasi
et al
.22 suggested that
the addition of NAC to triple therapy consisting of a PPI, cip-
rofloxacin, and bismuth increases the eradication rate by 9.3%,
they failed to demonstrate statistical significance. Until now,
all studies including the present study, regarding the adjuvant
effect of NAC on eradication therapy for
H. pylori
infection
were small pilot studies.16,17,22 Therefore, the results of this study
should not be interpreted as a failure of this regimen. Instead,
it could be used to determine the sample size needed to achieve
the planned power for testing our hypothesis. Based on the re-
sults of the present study, if we hypothesize that the eradication
rate of sequential therapy is 75% and the addition of NAC could
increase the eradication rate by 10%, in the setting of an alpha
of 0.05 and power of 80%, the estimated number of subjects
needed is 250 in each group.23 Therefore, larger studies are re-
quired to obtain conclusive results.
The eradication rate in SQT-only group in this study was un-
expectedly lower than those of previous studied performed in
Korea. We do not know the exact reason for this discrepancy;
however, we can speculate about it. An earlier Korean study
of sequential therapy between 2008 and 2009 reported high
eradication rates (85.9%/92.6% by ITT/PP analyses).24 However,
subsequent studies performed in our institution suggest decreas-
ing efficacy of sequential therapy in Korea. The eradication rate
of sequential therapy by ITT/PP analyses were 79.3%/81.9% be-
tween 2009 and 2010,25 75.6%/76.8% between 2011 and 2012,26
and 58.0%/70.0% between 2013 and 2014 in this study.27
These findings imply that resistance to antibiotics in
H. pylori
treatment is still increasing and that sequential therapy might
already be suboptimal in some regions. Therefore, more studies
are strongly required to develop a more effective regimen. In
addition, the low eradication rate in the SQT-only group by ITT
analysis could be explained in part by the high drop-out rate in
this group. Although controversy persists,
H. pylori
eradication
therapy tends to be more effective in patients with peptic ulcer
disease than in those with nonulcer dyspepsia.28,29 Therefore, the
very low proportion of patients with peptic ulcer disease among
those in this study also might have negatively influenced the ef-
ficacy of sequential therapy. In the present study, the PP eradi-
cation rate in patients with peptic ulcer disease was very high
in both SQT-only and SQT+NAC groups. However, the absolute
number of patients with peptic ulcer disease was too small to
allow us to draw significant conclusions in this subgroup.
One recent meta-analysis that evaluated the efficacy of se-
quential therapy in Asian adults reported that the rate of adverse
events of this regimen was 22.6%.10 The results of our study are
consistent with previous data (adverse event rate in the SQT-
only group, 26.2%). Furthermore, the addition of NAC did not
increase the adverse events of sequential therapy; this finding
Table 3.
Helicobacter pylori
Eradication Rates according to Disease
Categories
SQT-only SQT+NAC p-value
PUD
ITT analysis
Eradication rate, % 100 (5/5) 66.7 (6/9) 0.258
95% CI 34.0–99.4
PP analysis
Eradication rate, % 100 (5/5) 100 (6/6)
95% CI
NUD
ITT analysis
Eradication rate, % 48.0 (12/25) 58.3 (14/24) 0.571
95% CI 28.0–68.0 38.1–78.5
PP analysis
Eradication rate, % 63.2 (12/19) 70.0 (14/20) 0.741
95% CI 40.9–85.5 49.4–90.6
SQT-only, sequential therapy only; SQT+NAC, sequential therapy+N-
acetylcysteine; PUD, peptic ulcer disease; ITT, intention-to-treat; CI,
confidence interval; NUD, nonulcer dyspepsia; PP, per-protocol.
Table 4. Adverse Events
SQT-only
(n=42)
SQT+NAC
(n=41) p-value
Total, n (%) 11 (26.2) 11 (26.8) 0.947
Nausea or vomiting 3 2
Diarrhea 1 3
Dyspepsia 2 1
Epigastric soreness 4 0
Abdominal pain or discomfort 1 1
Dizziness 1 1
Metallic taste 1 1
Thirsty 1 1
Abdominal distension 0 1
Regurgitation 1 0
SQT-only, sequential therapy only; SQT+NAC, sequential therapy+N-
acetylcysteine.
524 Gut and Liver, Vol. 10, No. 4, July 2016
is also similar to the previous study.16 NAC is generally very
safe and classified as an over-the-counter drug. In this study,
we excluded patients with active peptic ulcer disease based on a
report that the administration of NAC induced gastric ulcers in
rats. However, this report is a very old one; it was published in
the 1980s. We could not find a subsequent article reporting this
adverse event in humans.30 In the present study, we used 800
mg/day of NAC in the SQT+NAC group based on the previous
human studies which used 60016,22 or 1,20017 mg/day of NAC.
Because NAC was very well tolerated in this study, to maximize
its effect, we are considering a study in which the dose of NAC
is 1,200 mg/day and the duration of administration is extended
to the entire period of sequential therapy. In addition, to add
NAC in the standard triple therapy also would be worth to try,
because surprisingly, no one tested this basic hypothesis in hu-
man.
This study has several limitations. First, although the total
number of enrolled patients fulfills a recommendation for sam-
ple size calculation in pilot studies that is to take more than 30
patients31 and the total number of patients is higher than that of
previous studies, it is still a pilot study. However, our findings
will be helpful in the design of new studies in this area. Second,
we could not performed culture for
H. pylori
due to a shortage
of manpower and cost issues. Therefore, we could not inves-
tigate the antibiotic resistance in each patient. However, we
believe that the randomized allocation of the subjects to both
groups would have overcome this weakness to some extent.
Third, due to the cost issues of placebo administration in the
SQT-only group, this study had an open-labeled design.
In conclusion, the eradication rate for
H. pylori
infection was
numerically higher in the SQT+NAC group than in the SQT-only
group. However, our data did not reach statistical significance,
indicating that larger trials are needed.
CONFLICTS OF INTEREST
No potential conflict of interest relevant to this article was
reported.
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