RESEARCH ARTICLE

A Multicenter, Randomized, Double-Blind,

Placebo-Controlled Trial of High-Dose
Rebamipide Treatment for Low-Dose Aspirin-
Induced Moderate-to-Severe Small Intestinal
Damage
Toshio Watanabe1*, Toshihisa Takeuchi2, Osamu Handa3, Yasuhisa Sakata4,
Tetsuya Tanigawa1, Masatsugu Shiba1, Yuji Naito3, Kazuhide Higuchi2,
Kazuma Fujimoto4, Toshikazu Yoshikawa3, Tetsuo Arakawa1
1 Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan,
2 Second Department of Internal Medicine, Osaka Medical College, Takatsuki, Osaka, Japan, 3 Department
of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan,
4 Department of Internal Medicine and Gastroenterology, Saga Medical School, Saga, Japan

* [email protected]
OPEN ACCESS

Citation: Watanabe T, Takeuchi T, Handa O, Sakata

Y, Tanigawa T, Shiba M, et al. (2015) A Multicenter,
Randomized, Double-Blind, Placebo-Controlled Trial Abstract
of High-Dose Rebamipide Treatment for Low-Dose
Aspirin-Induced Moderate-to-Severe Small Intestinal
Damage. PLoS ONE 10(4): e0122330. doi:10.1371/
journal.pone.0122330 Background
Academic Editor: John Green, University Hospital Low-dose aspirin (LDA) frequently causes small bowel injury. While some drugs have been
Llandough, UNITED KINGDOM reported to be effective in treating LDA-induced small intestinal damage, most studies did
Received: December 30, 2014 not exclude patients with mild damage thought to be clinically insignificant.
Accepted: February 10, 2015

Published: April 15, 2015 Aim

Copyright: © 2015 Watanabe et al. This is an open We conducted a multicenter, randomized, double-blind, placebo-controlled trial to assess
access article distributed under the terms of the
the efficacy of a high dose of rebamipide, a gastroprotective drug, for LDA-induced moder-
Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any ate-to-severe enteropathy.
medium, provided the original author and source are
credited.

Data Availability Statement: All relevant data are

Methods
within the paper and its Supporting Information files. We enrolled patients who received 100 mg of enteric-coated aspirin daily for more than 3
Funding: The authors have no support or funding to months and were found to have more than 3 mucosal breaks (i.e., erosions or ulcers) in the
report. small intestine by capsule endoscopy. Eligible patients were assigned to receive either
Competing Interests: YN has received research rebamipide 300 mg (triple dose) 3 times daily or placebo for 8 weeks in a 2:1 ratio. Capsule
grants from Eisai Co., Ltd., Otsuka Pharmaceutical endoscopy was then repeated. The primary endpoint was the change in the number of mu-
Co., Ltd and Takeda Pharmaceutical Co., Ltd. KH has
cosal breaks from baseline to 8 weeks. Secondary endpoints included the complete healing
received research grants and speaker’s fee from
Otsuka Pharmaceutical Co., Ltd. TA has received of mucosal breaks at 8 weeks and the change in Lewis score (an endoscopic score assess-
research grants from Eisai Co., Ltd. and Otsuka ing damage severity) from baseline to 8 weeks.

PLOS ONE | DOI:10.1371/journal.pone.0122330 April 15, 2015 1 / 12

 Aspirin-Induced Enteropathy and Rebamipide

Pharmaceutical Co., Ltd. Otsuka Pharmaceutical Co., Results

Ltd provided rebamipide and identical placebo. There
are no further patents, products in development or The study was completed by 38 patients (rebamipide group: n = 25, placebo group: n = 13).
marketed products to declare. This does not alter the After 8 weeks of treatment, rebamipide, but not placebo, significantly decreased the number
authors' adherence to all the PLOS ONE policies on of mucosal breaks (p = 0.046). While the difference was not significant (p = 0.13), the rate of
sharing data and materials.
complete mucosal break healing in the rebamipide group (32%, 8 of 25) tended to be higher
than that in the placebo group (7.7%, 1 of 13). Rebamipide treatment significantly improved
intestinal damage severity as assessed by the Lewis score (p = 0.02), whereas placebo did
not. The triple dose of rebamipide was well tolerated.

Conclusions
High-dose rebamipide is effective for the treatment of LDA-induced moderate-to-
severe enteropathy.

Trial Registration
UMIN Clinical Trials Registry UMIN000003463

Introduction
While it is prescribed widely for the primary or secondary prevention of cardiovascular or cere-
brovascular disease [1–3], low-dose aspirin (LDA) increases the risk of gastrointestinal ulcera-
tion and bleeding. In the last decade, concerns over this adverse effect of LDA focused mainly
on the upper gastrointestinal tract. However, several studies used video capsule endoscopy
(VCE) to show that LDA frequently causes injury to small bowel [4, 5], inducing intestinal
bleeding and anemia [6]. Thus, LDA-induced enteropathy has recently been recognized as
clinically significant.
Several clinical trials were performed with the aim of overcoming this adverse effect of LDA
on the small intestine, and some drugs were shown to effectively heal LDA-induced small intes-
tinal damage [4, 7, 8]. However, these studies did not exclude patients with mild damage
thought to be clinically insignificant. Furthermore, few randomized double-blind trials sup-
porting the efficacy of treatments for LDA-induced enteropathy have been reported.
Rebamipide (2-(4-chlorobenzoylamino-3-[2(1H)-quinolinon-4-yl] propionic acid)), a gas-
troprotective drug, has been clinically proven to effectively heal gastric ulcers [9] and prevent
non-steroidal anti-inflammatory drug (NSAID)-induced gastroduodenal damage [10]. Recent
studies using VCE have shown that rebamipide also has anti-ulcer effects in the small intestine,
preventing both LDA- and NSAID-induced enteropathy in healthy volunteers [11, 12]. This
suggests that rebamipide may also be effective in treating LDA-induced enteropathy. Impor-
tantly, Akamatsu et al. reported that rebamipide exhibited anti-ulcer effects via direct local
penetration from inside the stomach to the gastric mucosa, but not via systemic delivery after
absorption in the gastrointestinal tract [13]. Therefore, the ulcer-healing effect of rebamipide
on the small intestine appears weak at the standard dose of 300 mg/day, so a higher dose is
thought to be needed to successfully treat small intestine damage, especially LDA-induced se-
vere enteropathy. Although the dose of rebamipide currently approved for gastric ulcer and
gastritis is 300 mg/day, doses up to 900 mg/day were investigated in a phase II dose-finding
study conducted in Japan, and no safety problems were noted. Hence, we conducted a

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 Aspirin-Induced Enteropathy and Rebamipide

multicenter, randomized, double-blind, placebo-controlled trial to assess the efficacy of triple-

dose rebamipide in the treatment of LDA-induced moderate-to-severe small intestinal damage.

Methods
The protocol of this trial and the supporting CONSORT checklist are available as supporting
information; see S1 CONSORT Checklist and S1 Protocol.

Ethical approval
Before the start of the study, the Institutional Review Board of each participating institution re-
viewed and approved the protocol: The ethics committee of the Osaka City University Gradu-
ate School of Medicine (approval number, 1619); The ethics committee of the Osaka Medical
College (approval number, 705): The ethics committee of the Kyoto Prefectural University of
Medicine (approval number, C-633); and The ethics committee of the Saga Medical School
(approval number, 2012-10-01). Written informed consent was obtained from all participants

Study design
This Cytoprotection by REbamipide on Aspirin-induced Mid-GI damage (CREAM) study was
a multicenter, randomized, double-blind, placebo-controlled trial conducted to assess the effi-
cacy and safety of triple-dose rebamipide for LDA-induced moderate-to-severe small intestinal
damage. The study was carried out at 4 medical centers (Osaka City University Hospital,
Osaka Medical College Hospital, Kyoto Prefectural Medical University Hospital, and Saga Uni-
versity Hospital) in Japan from February 2011 through January 2014. The study was conducted
according to the Declaration of Helsinki and Good Clinical Practice guidelines. This trial was
registered in the UMIN Clinical Trials Registry as UMIN000003463.
Eligible patients were assigned to receive either rebamipide 300 mg 3 times daily or placebo
for 8 weeks in a 2:1 allocation ratio. Randomization was achieved by the minimization method,
and stratified by site of enrollment and use of concomitant antiplatelet drugs. After 8 weeks of
treatment with rebamipide or placebo, VCE was performed to assess the impact of treatment
on small intestinal damage.

VCE procedure
VCE was performed using the PillCam SB2 (Given Imaging, Ltd, Yoqneam, Israel). Patients
fasted for 12 h before swallowing the capsule. Fluids were permitted 2 h later, followed by a
light meal another 2 h later. Data were collected for up to 8 h after capsule ingestion. After 8 h,
the sensor array and recording device were removed. The VCE digital image stream was then
reviewed by 4 experts (Tetsuya T, Toshihisa T, OH, and YS). Since it is difficult to definitively
distinguish between erosions and ulcers (because VCE cannot accurately assess either lesion
size or depth), we combined them into a single category of injury (mucosal breaks).
In addition, the severity of LDA-induced enteropathy was assessed with the Lewis score
(LS) [14], a capsule endoscopic grading system of small intestinal mucosal inflammation and
damage. The detailed methods of calculating the LS have been previously described [14]. Small
bowel inflammatory changes were categorized into 3 groups according to the LS: normal or
clinically insignificant change (LS <135), mild mucosal inflammatory change (LS 135–790),
and moderate or severe change (LS >790).

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 Aspirin-Induced Enteropathy and Rebamipide

Patients
Male or female outpatients were eligible for the trial if they received 100 mg of enteric-coated
aspirin daily for more than 3 months for the primary or secondary prevention of cardiovascu-
lar and cerebrovascular disease and were found to have more than 3 mucosal breaks (i.e., ero-
sions or ulcers) in the small intestine by capsule endoscopy. Other inclusion criteria were an
age of at least 20 years and stable disease with no pressing need to change the current aspirin
regimen.
The main exclusion criteria included diseases that could induce small intestinal injury (such
as Crohn’s disease, gastrointestinal stromal tumors, and small intestinal tumors), use of
NSAIDs or anti-cancer drugs, the presence of diverticula and diaphragm-like stenosis in the
small intestine, and severe renal or hepatic dysfunction. Patients were also excluded if they
used antibiotics, sulfasalazine, prostaglandin (PG) analogs, corticosteroids, or gastroprotective
drugs, as these could potentially heal or worsen LDA-induced small intestinal damage. Patients
with ongoing overt gastrointestinal bleeding and those found to have active small intestinal
bleeding by VCE were also excluded.

Assessment
The primary endpoint was the change in the number of mucosal breaks from baseline to 8
weeks. Secondary endpoints included changes in the LS from baseline to 8 weeks, complete
healing of small intestinal mucosal breaks at 8 weeks, and changes in the levels of hemoglobin
and serum albumin from baseline to 8 weeks. Safety assessments included the documentation
of adverse events and clinical laboratory testing at baseline and after 4 and 8 weeks of
treatment.

Statistical analysis
Results are expressed as medians and interquartile ranges for continuous variables and percent-
ages for categorical variables. The characteristics of patients in the placebo and rebamipide
groups were compared using the χ2 test or Fisher exact test for categorical variables, whereas
quantitative variables were analyzed by the Mann–Whitney U-test. The Wilcoxon signed-rank
test (for continuous data) or McNemar test (for ordinal data) was used for comparisons of data
between baseline and 8 weeks. Differences with P-values <0.05 were considered significant. All
statistical analyses were performed using SPSS 21 for Windows (SPSS Inc.; Chicago, Illinois,
United States).

Sample size estimation

Sample size was estimated based on a previous study showing that the complete healing rate of
LDA-induced mucosal breaks was 58% in patients who took misoprostol, a PGE1 analog, for 8
weeks. The following assumptions were made for sample size calculation: (1) the wound-heal-
ing effect of a triple dose of rebamipide was equal to that of misoprostol; (2) the complete heal-
ing rates in the placebo and rebamipide groups were 20% and 58%, respectively; (3) 10% of
patients in each group will either drop out or have unsatisfactory follow-up VCE images. We
calculated that at least 30 patients were needed in the rebamipide group to give the study 90%
power at a 5% significance level by a test of proportions.

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 Aspirin-Induced Enteropathy and Rebamipide

Results
Subject enrollment and baseline characteristics
Between February 2011 and January 2014, 125 patients were assessed for study eligibility. In
total, 43 patients were enrolled and randomly assigned (in a 2:1 ratio) to the rebamipide group
(n = 29) or placebo group (n = 14). The study’s participant flow is shown in Fig 1. Five patients
were excluded because of cessation of LDA therapy during the trial (n = 2), incomplete visuali-
zation on the second capsule endoscopy (n = 1), patient’s intention to withdraw from the trial
(n = 1), and the development of overt gastrointestinal bleeding (n = 1).
Regarding gastrointestinal symptoms in the enrolled patients, one patient had abdominal
fullness at baseline, while the others were asymptomatic. At 8 weeks of treatment, all patients
who completed the trial were asymptomatic.
The patients’ baseline clinical characteristics were grouped according to treatment (Table 1).
There was no significant difference in baseline characteristics such as age, sex, body mass index,
smoking habit, and alcohol consumption between the placebo and rebamipide groups. In addi-
tion, the number of mucosal breaks at baseline did not differ between the two groups. Typical
photographs of mucosal breaks observed in this study are shown in Fig 2A and 2B.

Fig 1. Trial flow diagram.

doi:10.1371/journal.pone.0122330.g001

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 Aspirin-Induced Enteropathy and Rebamipide

Table 1. Baseline characteristics of patients.

Placebo (n = 13) Rebamipide (n = 25) P value

Median age (y) 74.8 74.1 0.93
Male sex, n (%) 9 (69.2) 16 (64.0) 1
Smoking habit, n (%) 1 (7.7) 4 (16) 0.64
Alcohol consumption, n (%) 4 (30.8) 10 (40) 0.73
Underlying diseases
ischemic heart disease, n (%) 8 (32) 15 (60) 0.8
ischemic cerebrovascular disease, n (%) 3 (23.1) 3 (12) 0.39
atherosclerosis, n (%) 1 (7.7) 4 (16) 0.64
others, n (%) 1 (7.7) 3 (12) 1
Complications
hypertension, n (%) 11 (84.6) 20 (80) 1
hyperlipidemia, n (%) 6 (46.2) 12 (48) 0.81
diabetes mellitus, n (%) 3 (27.3) 3 (12) 0.39
Proton pump inhibitor use, n (%) 7 (53.8) 12 (48) 1
H2 receptor antagonist use, n (%) 0 (0) 2 (8) 0.54
Concomitant use of other antiplatelets 2 (15.4) 3 (12) 0.11
Warfarin use, n (%) 1 (7.7) 3 (12) 1
ARB use, n (%) 7 (53.8) 12 (48) 1
Statin use, n (%) 6 (46.2) 12 (48) 0.81
Median number of mucosal breaks (IQR) 6 (4.0–18.5) 4 (3.0–8.0) 0.57
Median hemoglobin level (IQR) (g/dL) 13.1 (9.6–14.1) 12.9 (11.3–13.6) 1
Median albumin level (IQR) (g/dL) 4 (3.8–4.3) 4.2 (3.9–4.4) 0.78

ARB, angiotensin II receptor blocker; IQR, interquartile range.

doi:10.1371/journal.pone.0122330.t001

Primary endpoint
After 8 weeks of treatment, rebamipide significantly reduced the number of mucosal breaks
from 4.0 (3.0–8.0) to 2.0 (3.0–8.0, p = 0.046), whereas placebo did not result in a significant re-
duction (p = 0.08). The median number of mucosal breaks in the placebo group was 6.0 (4.0–
18.5) at baseline and 3.0 (2.0–15.0) at 8 weeks (Fig 3).

Secondary endpoints
Rebamipide treatment significantly improved the severity of intestinal damage as assessed by
the LS (p = 0.02), whereas placebo treatment did not alter the LS (p = 0.32, Fig 4). Eight (32%)
of 25 patients in the rebamipide group achieved complete healing of the intestinal mucosal
breaks at 8 weeks of treatment, compared with 1 (7.7%) of 13 patients in the placebo group.
The complete healing rate in the rebamipide group was higher than that in the placebo group,
although the difference did not reach statistical significance (p = 0.13). Neither group showed
significant changes from baseline to 8 weeks in hemoglobin and serum albumin levels
(Table 2).

Safety
Significant changes from the baseline values of any of the examined laboratory parameters
were recorded in both groups of patients. As described above, one patient in the placebo group

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 Aspirin-Induced Enteropathy and Rebamipide

Fig 2. Capsule endoscopic images of small bowel mucosal breaks induced by low-dose enteric-coated aspirin. Typical photographs of mucosal
breaks observed in this study are shown. A: a mucosal break (arrow). B: multiple mucosal breaks (arrows).
doi:10.1371/journal.pone.0122330.g002

developed overt gastrointestinal bleeding and discontinued the intervention (Fig 1); no other
adverse events were reported.

Discussion
Recent studies demonstrated the efficacy of several drugs such as rebamipide [12], misoprostol
[4] and a probiotic preparation, Lactobacillus casei strain Shirota [7], for LDA-induced enter-
opathy. However, these studies had shortcomings in terms of the subjects included. Some stud-
ies were conducted in young, healthy volunteers and evaluated preventive effects on LDA-
induced small intestinal damage. Even those studies that evaluated healing effects in chronic
LDA users enrolled patients with red spots but no mucosal breaks or patients with very few
mucosal breaks thought to be clinically insignificant. Furthermore, few randomized, double-
blind, placebo-controlled trials assessing the efficacy of treatments for LDA-induced intestinal
damage have been reported. In this study, we demonstrated that treatment with triple-dose
rebamipide could be effective therapy for LDA-induced enteropathy in patients who had more
than 3 mucosal breaks, and that this dose of rebamipide was well tolerated and did not cause
any adverse events. To the best of our knowledge, rebamipide is the first drug to show efficacy
for the treatment of LDA-induced moderate-to-severe enteropathy.
Recent studies greatly improved our understanding of the mechanisms underlying the path-
ogenesis of NSAID (including LDA)-induced small bowel damage. A mechanism of primary
importance for the onset of this damage is the inhibition of cyclooxygenase by NSAIDs, which
leads to collapse of the mucosal defensive system due to a reduction in PG synthesis. In addi-
tion, the topical effect of NSAIDs on the small bowel epithelium causes mitochondrial dysfunc-
tion, which also contributes to the disturbance of barrier function [15]. Once the mucosal
barrier has been disrupted, luminal Gram-negative bacteria enter the epithelium and release

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 Aspirin-Induced Enteropathy and Rebamipide

Fig 3. Changes in the number of small intestinal mucosal breaks from baseline to posttreatment. Results were analyzed by the Wilcoxon signed-
rank test.
doi:10.1371/journal.pone.0122330.g003

lipopolysaccharide [16], resulting in the induction of mucosal inflammatory responses such as

cytokine overexpression via the activation of the innate immune system [16–19]. This phe-
nomenon then triggers neutrophil infiltration with subsequent release of tissue proteolytic en-
zymes and reactive oxygen species, leading to intestinal ulceration.
Therefore, agents that interfere with any phase of the development of the damage are
thought to be useful in treating enteropathy [4, 20, 21]. Rebamipide has various effects on the
gastrointestinal tract [9, 22], which explains its efficacy against LDA- or NSAID-induced small
intestinal damage. It increases PG concentration via the induction of cyclooxygenase-2 [23, 24]
and has the potential to inhibit inflammatory cytokine expression [25] and neutrophil infiltra-
tion [26]. Rebamipide can also scavenge reactive oxygen species [27] and prevent indometha-
cin-induced mitochondrial damage in cultured gastric cells [28]. Furthermore, recent
experimental studies showed that rebamipide regulates small intestinal microbiota via the in-
duction of antimicrobial peptides [29, 30]. Thus, these effects of rebamipide appear to act in
concert to prevent and heal enteropathy.
There are a few limitations to this study. First, the sample size is relatively small. We there-
fore failed to find a significant difference in the complete healing rate of mucosal breaks

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 Aspirin-Induced Enteropathy and Rebamipide

Fig 4. Changes in the severity of small intestinal mucosal breaks from baseline to posttreatment. Results were analyzed by McNemar test.
doi:10.1371/journal.pone.0122330.g004

between the rebamipide and placebo groups, although we successfully demonstrated the effica-
cy of rebamipide in terms of the primary endpoint (i.e., reduction in the number of mucosal
breaks). The sample size of this trial was calculated based on our previous study in which treat-
ment with misoprostol resulted in complete healing in 58% of patients with LDA-induced

Table 2. Changes in the levels of hemoglobin and albumin after treatment with placebo or rebamipide.

Baseline After treatment P value

Median hemoglobin level (IQR) (g/dL)
Placebo 13.1 (9.6–14.1) 13.1 (11.0–14.1) 0.62
Rebamipide 12.9 (11.3–13.6) 13.2 (11.8–14.1) 0.19
Median albumin level (IQR) (g/dL)
Placebo 4.0 (3.8–4.3) 4.1(3.9–4.2) 0.14
Rebamipide 4.2 (3.9–4.4) 4.2 (4.1–4.3) 0.77

Results are expressed as medians and interquartile ranges (IQRs)

doi:10.1371/journal.pone.0122330.t002

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 Aspirin-Induced Enteropathy and Rebamipide

small intestinal mucosal breaks [4]. However, that study did not exclude patients with 1 or 2
mucosal breaks. As mentioned previously, we excluded such patients and enrolled only pa-
tients with more than 3 mucosal breaks, which may have reduced the complete healing rate in
this study. Further studies involving larger sample sizes are needed to determine the efficacy of
rebamipide for achieving complete healing of moderate-to-severe enteropathy. The second
limitation is our exclusion of patients with active small intestinal bleeding, which is a clinically
important condition. Therefore, a clinical trial that includes such patients should be performed
next. The other limitation is that we cannot deny the possibility that VCE missed some intesti-
nal lesions because the LDA-induced small intestinal mucosal breaks were relatively small. A
large-scale trial would be required to decrease the effect of this limitation.
In conclusion, triple-dose rebamipide is effective in the treatment of LDA-induced moder-
ate-to-severe enteropathy, and is well tolerated and safe. Since our study does not repudiate the
efficacy of standard dose rebamipide, a comparative study of standard and triple-dose rebami-
pide is needed to determine the appropriate dose of this drug for the treatment of LDA-in-
duced clinically significant small intestinal damage.

Supporting Information
S1 CONSORT Checklist. CONSORT Checklist.
(DOC)
S1 Protocol. Trial Protocol.
(DOC)

Author Contributions
Conceived and designed the experiments: TW YN KH KF TY TA. Performed the experiments:
TW T. Takeuchi OH YS T. Tanigawa. Analyzed the data: MS. Contributed reagents/materials/
analysis tools: TW T. Tanigawa. Wrote the paper: TW TA.

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