Gut and Liver, Vol. 8, No. 4, July 2014, pp.

371-379

ORIGINAL
ARTICLE

Preventive Efficacy and Safety of Rebamipide in Nonsteroidal

Anti-Inflammatory Drug-Induced Mucosal Toxicity

Jeong Ho Kim*,a, Soo-Heon Park*, Chul-Soo Cho†, Soo Teik Lee‡, Wan-Hee Yoo§, Sung Kook Kim", Young Mo Kang¶, Jong
Sun Rew#, Yong-Wook Park**, Soo Kon Lee††, Yong Chan Lee‡‡, Won Park§§, and Don-Haeng Lee""
Departments of *Gastroenterology, †Rheumatology, Yeouido St. Mary’s Hospital, The Catholic University of Korea College of Medicine, Seoul,
Departments of ‡Gastroenterology, §Rheumatology, Chonbuk National University Hospital, Chonbuk National University Medical School,
Jeonju, Departments of ∥Gastroenterology, ¶Rheumatology, Kyungpook National University Hospital, Kyungpook National University School
of Medicine, Daegu, Departments of #Gastroenterology, **Rheumatology, Chonnam National University Hospital, Chonnam National University
Medical School, Gwangju, Departments of ††Rheumatology, ‡‡Gastroenterology, Severance Hospital, Yonsei University College of Medicine,
Seoul, Departments of §§Rheumatology and ∥∥Gastroenterology, Inha University Hospital, Inha University School of Medicine, Incheon, Korea

Background/Aims: The use of proton pump inhibitors vs 21.9%, p=0.6497) according to ITT analysis. In
or misoprostol is known to prevent the gastrointestinal addition, the therapeutic failure rate was similar in the
compli- cations of nonsteroidal anti-inflammatory drugs rebamipide and misoprostol groups (13.6% vs 13.1%,
(NSAIDs). Rebamipide is known to increase the mucosal p=0.8580). The total severity score of the
generation of prostaglandins and to eliminate free gastrointestinal symptoms was significantly lower in the
oxygen radicals, thus enhancing the protective function rebamipide group than in the miso- prostol group
of the gastric mucosa. However, it is unknown whether (p=0.0002). The amount of antacid used was significantly
rebamipide plays a role in preventing NSAID-induced lower in the rebamipide group than in the miso- prostol
gastropathy. The aim of this study was to determine the group (p=0.0258). Conclusions: Rebamipide can prevent
effectiveness of rebamipide compared to misoprostol in gastric ulcers when used with NSAIDs and can de- crease
preventing NSAID-induced gastrointestinal complications the gastrointestinal symptoms associated with NSAID
in patients requiring continuous NSAID treat- ment. administration. When the possibility of poor compliance
Methods: We studied 479 patients who required con- and the potential adverse effects of misoprostol are
tinuous NSAID treatment. The patients were randomly considered, rebamipide appears to be a clinically effective
as- signed to groups that received 100 mg of rebamipide and safe alter- native. (Gut Liver 2014;8:371-379)
three
times per day or 200 μg of misoprostol three times per day
for 12 weeks. The primary endpoint of the analysis was Key Words: Anti-inflammatory agents, non-steroidal;
the occurrence rate of gastric ulcers, as determined by Rheu- matic diseases; Complications; Rebamipide;
endosco- py after 12 weeks of therapy. Results: Of the 479 Misoprostol
patients in the study, 242 received rebamipide, and 237
received miso- prostol. Ultimately, 44 patients (18.6%) INTRODUCTION
withdrew from the misoprostol group and 25 patients
(10.3%) withdrew from the rebamipide group. There was Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely
a significant difference in withdrawal rate between the two prescribed for several conditions, including rheumatoid arthritis,
groups (p=0.0103). The per protocol analysis set was not osteoarthritis, and musculoskeletal injuries.1 The administration
valid because of the dropout rate of the misoprostol of NSAIDs, however, can cause gastrointestinal
group; thus, the intention to treat (ITT) analysis set is the complications, such as bleeding, ulceration, perforation, and
main set for the efficacy analysis in this study. After 12 obstruction. The factors that increase the risk of NSAID-
weeks, the occurrence rate of gastric ulcers was similar in induced gastrointesti- nal complications include age over 60
the rebamipide and misoprostol groups (20.3% years, concomitant use of systemic corticosteroids, or
anticoagulants, and a history of

Correspondence to: Soo-Heon Park

Department of Gastroenterology, Yeouido St. Mary’s Hospital, The Catholic University of Korea College of Medicine, 10 63-ro, Yeongdeungpo-
gu, Seoul 150-713, Korea
Tel: +82-2-3779-1328, Fax: +82-2-3779-1331, E-mail: [email protected]
Received on January 28, 2013. Revised on June 16, 2013. Accepted on July 5, 2013. Published online on December 24, 2013
pISSN 1976-2283 eISSN 2005-1212 http://dx.doi.org/10.5009/gnl.2014.8.4.371
a
Current affiliation: Division of Gastroenterology, Department of Internal Medicine, Myongji Hospital, Seoul, Korea
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0)
which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
372

peptic ulcer.2-6 NSAID-induced gastrointestinal complications (abnormalities in platelets or blood clotting

are caused by various mechanisms, such as abnormalities in
prostaglandin-dependent gastric mucosal protection caused
by decreased gastric mucosal prostaglandins.7
Cyclooxygenase 2 (COX-2) inhibitors, which are known to
be safer than other NSAIDs, are used to reduce NSAID-
induced gastrointestinal side effects. Many doubts still exist,
however, about the clinical safety of COX-2 inhibitors, as
illustrated by the removal of the COX-2 inhibitor rofecoxib
from the market.8 Cotherapy with misoprostol or proton pump
inhibitors (PPIs) is another way to prevent NSAID-induced
gastrointestinal compli- cations; however, misoprostol itself
can cause side effects, such as abdominal pain, diarrhea, and
dyspepsia, which can decrease medication compliance.1
Long-term PPI administration is also problematic because
issues such as osteoporosis, aspiration pneumonia, and
atrophic gastritis may result.9
Rebamipide is an antiulcer drug that protects gastric
epithelial cells, improves gastric defense mechanisms by
increasing gastric mucus, increases prostaglandin production,
and reduces free ox- ygen radicals.10-13 In healthy volunteers,
rebamipide is effective at preventing the gastric injury
caused by the administration of indomethacin. Although the
preventive effects of rebamip- ide on NSAID-induced
gastropathy are equivalent to those of misoprostol,
rebamipide has been reported to cause fewer side effects
(e.g., lower incidences of diarrhea, lower abdominal pain, and
abdominal distension).14,15 The present study evaluated the
efficacy and safety of rebamipide for preventing gastrointestinal
complications due to NSAIDs by comparing it with
misoprostol in a randomized, multicenter, double-blind study
of patients with a high risk of NSAIDs complications.

MATERIALS AND METHODS

1. Patients

The present study was conducted in patients who

presented at the Yeouido St. Mary’s Hospital of The Catholic
University of Korea College of Medicine and 16 other
hospitals from January 2008 to March 2010. The inclusion
criteria were patients over the age of 19 years who had
rheumatoid arthritis, osteoarthritis, ankylosing spondylitis,
and other joint diseases that require continuous
administration of NSAIDs for more than 12 weeks. Patients
with a modified Lanza score below 3 in an upper
gastrointestinal endoscopy who did not have current
gastroin- testinal symptoms and who had at least one of the
following ulcer risk factors were selected for the study
population: his- tory of peptic ulcer identified through an
upper gastrointestinal endoscopy, over the age of 60 years,
and concomitant therapy with systemic corticosteroids
(taking more than 5 mg/day of prednisolone or the equivalent
dose of steroid).16 The following exclusion criteria were used:
patients with a history of gastroin- testinal surgery (except
appendectomy); patients with abnormal bleeding tendency
 373
factors); patients with active gastroduodenal ulcers, gastro-
esophageal reflux disease, gastroesophageal varices,
Barrett’s esophagus, esophageal strictures, or malignant
tumors in an upper gastrointestinal endoscopy; patients
diagnosed with mal- absorption within the last 3 months;
patients with a history of cerebrovascular disease, coronary
artery disease, diabetes mel- litus, pancreatitis, chronic
kidney disease, chronic liver disease, or malignant tumors;
patients who were using medications that affect
gastrointestinal motility, such as sucralfate, H2-receptor
antagonists, misoprostol, and prokinetics, within a week of
participating in the study; patients who were using aspirin
or anticoagulants; patients who were using a PPI within 2
weeks of participating in the study; pregnant or nursing
women; and women of childbearing age who were not
using a medically confirmed method of contraception.
Before the clinical trial was conducted, the protocols, in-
formed consent forms, and all other related matters were
ap- proved by the Korea Food and Drug Administration
and the Institutional Review Board of the corresponding
institution that was conducting the clinical trial.

2. Methods

This study was as a double-blind, double-dummy,

random- ized, multicenter, parallel comparison clinical trial.
This study consisted of a screening period for 1 or 2 weeks
before enroll- ment, treatment period for 12 weeks, and
safety follow-up peri- od for the 30 days after last
investigational product (IP) admin- istration (Fig. 1). The
subjects who agreed to participate and met the inclusion
criteria were randomly assigned to either the treat- ment
(rebamipide) or control (misoprostol) group. The treatment
group received 100 mg of rebamipide three times a day,
and the control group received 200 μg of misoprostol three
times a day for 12 weeks. As for NSAIDs, after stopping
NSAIDs taken currently for 1 to 2 weeks, one of
medications in the following, which fits a subject, was
administered for 12 weeks from the randomization day:
100 mg of aceclofenac twice a day, 15 mg of meloxicam
once a day, or 1,000 mg of nabumetone once a day (Table
1). An upper gastrointestinal endoscopy was per- formed
during screening and 12 weeks after the IP administra- tion
to evaluate the efficacy. To evaluate safety, vital signs and
blood chemistry were assessed during every visit from
screening period to the last day of IP administration. The
subjects with major protocol deviation (e.g., less than 80% IP
compliance and not taking NSAIDs for 5 consecutive days)
were excluded from the per protocol (PP) analysis set.
Taking the following concomitant medications which can
af-
fect the clinical symptoms or efficacy evaluation was
prohibited: anticholinergic drugs, H2-receptor antagonists,
PPIs, sucralfate, prokinetics, antacids (except aluminum
hydroxide gel, which was allowed as a rescue medication),
prostaglandin drugs other than misoprostol, other drugs
affecting gastric acid secretion and gastrointestinal
motility, anticancer drugs, anticoagulants,
374

Fig. 1. Study design.

AE, adverse event; SAE, serious adverse event; CM, concomitant medication; F/U, follow-up.

Table 1. Nonsteroidal Anti-Inflammatory Drugs That Were Prescribed sumed to be 3.7%. The clinically acceptable margin () for
in the PRESENT Study (Intention to Treat Population) noninferiority trial was assumed to be 6.9%1,17 because 6.9% is
Misoprostol Rebamipide Total half of 13.8%, which is the difference between the
Prescribed NSAIDs (n=237) (n=242) p-value*
(n=479) occurrence rate of gastric ulcer of placebo (17.5%) and
misoprostol (3.7%).
Aceclofenac (100 mg) 75 (31.7) 60 (24.8) 135 (28.2) 0.2489 Assuming a significance level () of 0.025 in a one-sided test,
Meloxicam (7.5 mg) 117 (49.4) 132 (54.6) 249 (52.0) a statistical power (1-) of 90%, and a 1:1 treatment to control

Nabumetone (500 mg) 45 (19.0) 50 (20.7) 95 (19.8) group ratio, the number of subjects (n) required for each
Data are presented as number (%). group was 158. Assuming a dropout rate of 20%, the total
NSAID, nonsteroidal anti-inflammatory drug. number of subjects was set to 396 (198 in each group).
*Chi-square test.
The efficacy variables included the occurrence rate of
gastric ulcer, the frequency and rate of the therapeutic
failure. For the occurrence rate of gastric ulcer and the
and NSAIDs other than those provided by the sponsor. therapeutic failure rate, frequency and percentage of the
The primary efficacy endpoint was the occurrence rate of occurrence of gastric ulcer and the therapeutic failure were
gastric ulcer confirmed on gastrointestinal endoscopy that obtained, and the comparison of their rate between groups
was performed 12 weeks after the IP administration. An were performed using chi-square test. A repeated measures
ulcer was defined as an excavated mucosal layer with a analysis of variance was used to compare the severity of
diameter of greater than 3 mm. The occurrence rate of gastric gastrointestinal symptoms between the two groups. A two-
ulcer was de- termined with the following equation: (the sample t-test or Wilcoxon rank sum test was used to compare
number of subjects with gastric ulcer/the total number of amount of antacid consumption between the two groups.
subjects in the analysis set)×100. The therapeutic failure rate, For the percentage of the subjects who experienced
the severity of gastrointes- tinal symptoms, and the amount of adverse events (AEs) more than once, a 95% confidence
antacid used were evaluated as secondary efficacy endpoints. interval was obtained and the difference between groups was
Therapeutic failure was defined as developing a gastric ulcer compared us- ing chi-square test or Fisher exact test. SAS
or withdrawal due to intractable gastrointestinal symptoms, version 9.1 (SAS Institute, Cary, NC, USA) was used to
which might be major side effect of misoprostol. perform the statistical analysis.
The gastrointestinal symptoms consisted of seven items:
heartburn, abdominal distention, nausea, vomiting, upper ab- RESULTS
dominal pain, lower abdominal pain, and diarrhea. To
compare the total severity score of gastrointestinal 1. Patient population
symptoms between the two groups, each item was evaluated A total of 664 patients from 17 sites received a screening
as no symptoms (0 points), mild symptoms (1 point), moderate test. Among the 664 patients, 185 were excluded, and 479
symptoms (2 points), or severe symptoms (3 points). The were de- termined to meet the inclusion criteria. Of the 479
amount of antacid used (the total number of tablets taken) in patients, 237 were randomly assigned to the control
the two groups during the clinical trial was compared. (misoprostol) group, and 242 were assigned to the treatment
3. Statistics (rebamipide) group. Four hundred seventy-eight subjects
received the IP at least once (one subject in the misoprostol
From the results of previous clinical studies of group did not), and 410 subjects com- pleted the clinical trial:
misoprostol (the control drug), the occurrence rate of gastric 193 subjects in the misoprostol group and 217 subjects in the
ulcer was as- rebamipide group (Fig. 2). Sixty-nine of
 375

Fig. 2. Subject dispositions. *One

subject had multiple reasons for
screening failure (inclusion/exclu-
sion criteria were not respected,
and others).

Table 2. Withdrawal Rates in the PRESENT Study (Intention to Treat (Table 3).
Population)
2. Treatment efficacy
Reason for Misoprostol Rebamipide Total
p- value
dropping out (n=237) (n=242) (n=479)
*
1) Primary efficacy endpoint
The primary efficacy endpoint was the occurrence rate of
AEs 10 4 14
gastric ulcer from the upper gastrointestinal endoscopy (i.e.,
Poor compliance with
1 3 4 the percentage of subjects in each analysis set with a
the protocol
confirmed gastric ulcer). The subject who missed the
Consent 33 15 48 gastrointestinal en- doscopy evaluation in 12 weeks of IP
withdrawal†
administration due to the withdrawal was regarded as the
Other 0 3 3 subject with gastric ulcer (ther- apeutic failure) in the ITT
Total, no. (%) 44 (18.6) 25 (10.3) 69 (14.4) 0.0103 analysis set. The occurrence rate of gastric ulcer did not
AE, adverse event.† significantly differ in the ITT analysis set: 21.9% (52/237
subjects) for the misoprostol group and 20.3%
*Chi-squared test; Intractable gastrointestinal symptoms and insuf-
ficient pain (49/242 subjects) for the rebamipide group (p=0.6497) (Table 4).
control.

2) Secondary efficacy endpoints

the randomly assigned subjects withdrew from the trial: 44 The secondary efficacy endpoints were therapeutic failure
sub- jects in the misoprostol group (18.6%) and 25 subjects in rate, the severity of gastrointestinal symptoms, and the
the re- bamipide group (10.3%). The withdrawal rate was amount of antacid used. The therapeutic failure rates did not
significantly greater in the misoprostol group compared with signifi- cantly differ between the two groups: 13.1% (31/237
the rebamipide group (p=0.0103 in a chi-square test). The subjects) for the misoprostol group and 13.6% (33/242
patients provided the following reasons for withdrawal: 14 subjects) for the rebamipide group (p=0.8580) (Table 5).
subjects withdrew because of AE (10 in the misoprostol The total severity score of gastrointestinal symptom in the
group and four in the rebamipide group), four subjects misoprostol group were 0.33±0.59 before IP administration,
withdrew because of poor protocol compli- ance (one in the 0.80±1.14 at 4 weeks, 0.67±1.19 at 8 weeks, and 0.67±1.24
misoprostol group and three in the rebamipide group), and 48 at 12 weeks. The total severity scores in the rebamipide group
subjects withdrew because of the withdrawal due to were generally lower than those in the misoprostol group:
gastrointestinal pain (33 in the misoprostol group and 15 in 0.24±0.54 before IP administration, 0.44±0.92 at 4 weeks,
the rebamipide group) (Table 2). Therefore, the major 0.36±0.78 at 8 weeks, and 0.44±1.05 at 12 weeks. In the
analysis set for the efficacy in this study is the intention to repeated measures analysis of variance, the severity of
treat (ITT) analysis set because the PP analysis set is decided gastrointestinal symptoms was significantly lower in the
as less valid than ITT analysis set due to significant rebamipide group compared with the misoprostol group (a
difference in the with- drawal rate in between the two significant group effect, p=0.0002) (Table 6).
groups. There were no signifi- cant differences between the In the ITT analysis,the number of antacid tablet was
groups regarding age, sex, smok- ing history, ulcer risk 11.18±22.79 for the misoprostol group and 7.19±15.49 for
factors, or modified Lanza scores from the endoscopy. The the rebamipide group (p=0.0258) (Table 7).
prevalence of ankylosing spondylitis, however, was
significantly greater in the misoprostol group (p=0.0358)
376

Table 3. Demographic Characteristics of the Study Patients

Misoprostol Rebamipide Total
Characteristic p-value
(n=237) (n=242) (n=479)
Age, yr 55.8±12.2 55.8±12.2 55.8±12.2 0.9640*
Sex
Male 44 (18.6) 42 (17.4) 86 (18.0) 0.8119†
Female 193 (81.4) 200 (82.6) 393 (82.1)
‡
Smokers 36 (15.2) 42 (17.4) 78 (16.3) 0.5383†
Risk factors
Peptic ulcer history 27 (11.4) 21 (8.7) 48 (10.0) 0.3627†
60 Years of age 124 (52.3) 118 (48.8) 242 (50.5) 0.4652†
Concomitant use of 132 (55.7) 153 (63.2) 285 (59.5) 0.0951†
systemic corticosteroids
Concomitant disease
Rheumatoid arthritis 149 (62.9) 160 (66.1) 309 (64.5) 0.5040†
Osteoarthritis 79 (33.3) 79 (32.6) 158 (33.0) 0.9226†
Ankylosing spondylitis 14 (5.9) 5 (2.1) 19 (4.0) 0.0358†
Other§ 43 (18.1) 40 (16.5) 83 (17.3) 0.7174†
Modified Lanza score
(from the screening endoscopy)
Grade 0 124 (52.3) 132 (54.6) 256 (53.4) 0.1636†
Grade 1 48 (20.3) 55 (22.7) 103 (21.5)
Grade 2 40 (16.9) 24 (9.9) 64 (13.4)
Grade 3 25 (10.6) 30 (12.4) 55 (11.5)
Grade 4 0 0 0
"
Grade 5 0 1 (0.4) 1 (0.2)
Data are presented as mean±SD or number (%).
*Two-sample t-test; †Fisher exact test; ‡Smokers were defined as individuals who reported any tobacco use; §Osteoporosis, systemic lupus erythem-
atous, and spinal stenosis; "Major deviation from the inclusion criteria.

Table 4. Occurrence Rate of Gastric Ulcer at 12 Weeks administration dayFailure

Table 5. Therapeutic until
Rates30in thedays (afterandthe last
Misoprostol
Rebamipide Groups
administration day); and exacerbation of pre-existing
Ulcer prevalence
3. Safety evaluation 95% two-
Population Misoprostol Rebamipide p-value* symptoms or AEs which the subject experienced
Misoprostol Rebamipide initially after
sided CI p-value*
The safety evaluation
(n=237) was
(n=242)conducted with the 478 IP administration (TEAE).(n=237) (n=242)
During the clinical trial period, 805
subjects who were randomized and received IP at least once. AEs Therapeutic in †331 31
occurredfailure of (13.1) 33 (13.6)(69.3%):
the 478 subjects 0.8580
166
ITT† 52 (21.9) 49 (20.3) 0.6497 -9.00-5.61
One of subjects had excluded on the safety evaluation misoprostol subjects
Data are presented (70.3%,
as number 400
(%).
Data are presented as number (%). *Chi-squared test; †rebamipide
Therapeutic failures include gastric405
ulcers and pa-
because the subject couldn’t take an IP. All the AEs which events) and 165 subjects (68.2%, events).
CI, confidence interval; ITT, intention to treat. tients dropping out because of intractable gastrointestinal symptoms.
occurred in test;
*Chi-squared this †Missing
study were classified
endoscopy into
results at nontreatment
12 weeks were There were 720 TEAEs in 319 subjects (66.7%), and the
con- sidered to be ulcers.
emergent adverse event (non-TEAE) occurring before incidence of these events did not significantly differ between
administration of the IP and from the day corresponding to the groups: 161 subjects for misoprostol (68.2%, 373 events)
five times the half-life after the last and 158 subjects for rebamipide (65.3%, 347 events).
However, the majority of
 377

Table 6. Gastrointestinal Symptom Severity in the Misoprostol and Rebamipide Groups

Gastrointestinal Misoprostol Rebamipide

Visit p-value*
symptoms No. Mean±SD No. Mean±SD
ITT (LOCF) Baseline 237 0.33±0.59 242 0.24±0.54 0.0002
4 wk 218 0.80±1.14 236 0.44±0.92
8 wk 218 0.67±1.19 236 0.36±0.78
12 wk 218 0.67±1.24 236 0.44±1.05
ITT, intention to treat; LOCF, last observation carried forward.
*Repeated-measures analysis of variance.

Table 7. Number of Subjects Who Consumed Antacid during the 12 Weeks of Nonsteroidal Anti-Inflammatory Drug Administration
Misoprostol Rebamipide Total p-value
The no. of subjects in the ITT population 237 242 479
Antacid consumption 114 (48.1) 96 (39.7) 210 (43.8) 0.0630*
The total no. of antacid tablets consumed per subject †
11.18±22.79 7.19±15.49 9.16±19.53 0.0258‡
Data are presented as number (%) or mean±SD.
ITT, intention to treat.
*Chi-squared test; †Subjects who did not take antacids were regarded as having taken 0 tablets; ‡Two-sample t-test.

Table 8. Treatment Emergent Adverse Events and Adverse Events in the Rebamipide and Misoprostol Groups
TEAEs AEs*
Misoprostol Rebamipide Total Misoprostol Rebamipide Total
(n=236) (n=242) (n=478) (n=236) (n=242) (n=478)
Total no., subjects (%) [events] 161 (68.2) 158 (65.3) 319 (66.7) 166 (70.3) 165 (68.2) 331 (69.3)
[373] [347] [720] [400] [405] [805]
Exact 95% CI 61.9-74.1 58.9-71.3 62.3-70.9 64.1-76.1 61.9-74.0 64.9-73.4
p-value† 0.4988 0.6215
No. of AEs
Mild 284 (76.1) 295 (85.0) 579 (80.4) 307 (76.8) 347 (85.7) 654 (81.2)
Moderate 74 (19.8) 45 (13.0) 119 (16.5) 78 (19.5) 48 (11.9) 126 (15.7)
Severe 15 (4.0) 7 (2.0) 22 (3.1) 15 (3.8) 10 (2.5) 25 (3.1)
Serious AEs, 3 (1.3) 7 (2.9) 10 (2.1) 3 (1.3) 10 (4.1) 13 (2.7)
subjects (%) [events] [3] [9] [12] [3] [13] [16]
Exact 95% CI 0.3-3.7 1.2-5.9 1.0-3.8 0.3-3.7 2.0-7.5 1.5-4.6
p-value† 0.3389 0.0882
Data are presented as number (%).
TEAE, treatment emergent adverse event; AE, adverse event; CI, confidence interval.
*All of the AEs (including the TEAEs) during the study; †Fisher exact test.

the rebamipide group’s TEAEs were mild (misoprostol group,

testinal disorders: 64 subjects (27.1%) in the misoprostol
76.1% [284/373 events]; rebamipide group, 85.0% [295/347
group and 47 subjects (19.4%) in the rebamipide group;
events]), and the proportion of moderate or severe TEAEs was
however, the difference was not statistically significant.
higher in the misoprostol group (misoprostol group, 23.9%
Nausea was signifi- cantly more common in the misoprostol
[89/373 events], rebamipide group, 15.0% [52/347 events])
group (15 subjects, 6.4%) compared with the rebamipide
(Table 8).
group (four subjects, 1.7%) (p=0.0095) (Table 9).
The most common adverse drug reaction (ADR) was
gastroin-
378

Table 9. Major Treatment Emergent Adverse Events Related to the

Study Drug of Subjects in Either Treatment Group by System Organ
Class and Preferred Term
Misoprostol Rebamipide Total
p-value*
(n=236) (n=242) (n=478)
Total no. of TEAEs 69 (29.2) 53 (21.9) 122 (25.5) 0.0746
[126] [95] [221]
Gastrointestinal
disorders
Upper abdominal 42 (17.8) 38 (15.7) 80 (16.7) 0.5432
pain [56] [45] [101]
Abdominal 12 (5.1) 8 (3.3) 20 (4.2) 0.3680
distension [12] [9] [21]
Nausea 15 (6.4) 4 (1.7) 19 (4.0) 0.0095
[19] [4] [23]
Diarrhea 10 (4.2) 5 (2.1) 15 (3.1) 0.1980
[11] [10] [21]
Data are presented as subjects (%) [events].
Fig. 3. Time to first adverse event (AE) (safe population).
TEAE, treatment emergent adverse event.
*Fisher exact test.

DISCUSSION the lansoprazole groups had a significant (p<0.001) gastric

ulcer protective effect compared with the placebo group, the
Approximately 10% to 60% of patients who take NSAIDs protec- tive effect was significantly smaller (p=0.01 and
experience gastrointestinal symptoms (e.g., abdominal pain, p=0.04 for the 15 and 30 mg groups, respectively) than the
heartburn, bloating, and indigestion). Interestingly, 10% to effect of miso- prostol. However, the misoprostol group had
20% of the rheumatoid arthritis patients who start NSAIDs several early trial withdrawals due to AEs. When these
discon- tinue them due to gastrointestinal symptoms.18 Thus, withdrawals were regarded as therapeutic failures, the
preventing gastrointestinal symptoms (in addition to successful treatment percentages were 69% for the
preventing peptic ul- cers) is an important treatment goal in misoprostol group, the 15 mg lansoprazole group, and the
patients taking NSAIDs. It is difficult to obtain an accurate 30 mg lansoprazole group and 35% for the pla- cebo group.19
incidence for NSAID-induced ulcers because many cases are Given the low medication compliance and high
asymptomatic. In an upper gas- trointestinal endoscopy study gastrointestinal-related AE rates for misoprostol,
of patients taking NSAIDs, gastric ulcers occurred in 10% to lansoprazole was judged to have high practical clinical value
40% of the patients within the first 3 months of NSAID use, in patients us- ing NSAIDs for extended periods; therefore, it
and duodenal ulcers were reported in 4% to 15% of the was approved by the U.S. Food and Drug Administration in
cases.19 November 2011.
A PP analysis is not regarded as a valid in the current The misoprostol group may have more patients who withdrew
study due to the significantly greater number of patients in early due to gastrointestinal pain because of gastrointestinal
the miso- prostol group who withdrew compared with the symptoms from incipient gastric ulcers. Furthermore, the time to
rebamipide group. In a previous lansoprazole study, the ITT the first AE in the patients who dropped out was 36 days for
results were also used as the primary analysis because the the misoprostol group and 56 days for the rebamipide group,
PP analysis was not valid due to significant difference in the and the more rapid onset of AEs in the misoprostol group
withdrawal rate in between the two groups.19 In the ITT may have affected the withdrawal rate (Fig. 3). In addition to
analysis of the current study, the occurrence rate of gastric misoprostol, PPI cotherapy is used to prevent NSAID-induced
ulcer in the misoprostol group (21.9%, 52/237 subjects) was gastrointesti- nal injury. According to recent data from
not significantly differ- ent (p=0.6497) from the rate in the Cochrane, the preva- lence of endoscopically confirmed
rebamipide group (20.3%, 49/242 subjects). gastric ulcers after 12 weeks of NSAIDs and PPI cotherapy is
In a previous study about the efficacy of the PPI drug 12.8% to 19.1%.20 In case of misoprostol, the gastric ulcer
lanso- prazole to prevent NSAID-induced gastric ulcers, the prevalence due to NSAIDs has been found to be 8.1% to
percent- ages of subjects without gastric ulcers after 12 weeks 10.5%.17 When a group of patients at high risk for
of medica- tion were 51% for the placebo group, 93% for the gastrointestinal complications received NSAIDs for 12 weeks
misoprostol group (200 μg four times/day), 80% for the 15 in the current study, the occurrence rate of gastric ulcer in the
mg lansoprazole group, and 82% for the 30 mg lansoprazole rebamipide group was 11.1% in the PP analysis set, which
group. Although did not differ from previously reported occurrence rate of
gastric ulcer for PPIs. This result suggests that rebamipide is
 379

able to prevent gastric ulcer complications with an efficacy

In conclusion, cotherapy with the mucosal protective
that is similar to that of PPIs when it is administered for 12
agent rebamipide can safely and effectively prevent gastric
weeks to patents at high risk for NSAIDs complications.
ulcers in high-risk patients who require long-term NSAID
Furthermore, the use of rebamipide could be a cost-effective
administration.
method of prevent- ing NSAID-induced gastrointestinal
complications in Korea.
CONFLICTS OF INTEREST
Even when we regarded the withdrawal due to gastroin-
testinal injuries (the major AE for misoprostol) as a
No potential conflict of interest relevant to this article was
treatment failure, the therapeutic failure rates in the
reported.
misoprostol and the rebamipide groups (13.1% and 13.6%,
respectively) were not significantly different. However, the
ACKNOWLEDGEMENTS
severity of gastrointestinal symptoms in the rebamipide group
was significantly lower dur- ing the 12 weeks of NSAIDs
The authors would like to thank the following researchers
administration. Therefore, rebamip- ide can effectively
their participation and assistance with this study:
improve the gastrointestinal symptoms that occur with
Myung-Gyu Choi, Department of Gastroenterology, Seoul
NSAIDs use. Because misoprostol decreases medica- tion
St. Mary’s Hospital, The Catholic University of Korea College
compliance due to gastrointestinal symptoms from the drug
of Medicine, Seoul, Korea.
itself, rebamipide is thought to be a more appropriate
Yeong-Wook Song, Department of Rheumatology, Seoul
medica- tion for preventing NSAIDs complications. The
Na- tional University Hospital, Seoul, Korea.
rebamipide group also had significantly lower antacid
Jin Hong Kim, Department of Gastroenterology, Ajou
consumption. Thus, the clinical usefulness of rebamipide is
Univer- sity Hospital, Suwon, Korea.
thought to be superior to that of misoprostol for patients who
Seung-Cheol Shim, Department of Rheumatology, Eulji Uni-
take NSAIDs for extended periods.
versity Hospital, Daejeon, Korea.
According to the safety analysis, nausea was more
Sang Young Seol, Department of Gastroenterology, Inje
common
in the misoprostol group compared with the rebamipide Uni- versity Busan Paik Hospital, Inje University College of
group. Although ADRs during the NSAIDs cotherapy Medicine, Busan, Korea.
occurred less frequently in the rebamipide group compared Jung-Soo Song, Department of Rheumatology, Chung-
with the miso- prostol group, the difference between the two Ang University College of Medicine, Seoul, Korea.
groups was not significant. This result was confirmed in the Jun-Ki Min, Department of Rheumatology, Bucheon St.
Cochrane Database of Systematic Reviews and in the existing Mary’s Hospital, The Catholic University of Korea College of
literature.20,21 The Cochrane Database of Systematic Reviews Medicine, Bucheon, Korea.
has reported that misoprostol increases the dropout risk due Han Joo Baek, Department of Rheumatology, Gachon
to AEs (especially nausea, diarrhea, and abdominal pain) by Univer- sity of Medicine and Science, Incheon, Korea.
1.6-fold.20 Moreover, in a 6-month study of the prevention of Seung Jae Hong, Department of Rheumatology, Kyung Hee
serious NSAID-induced gastrointestinal complications, the University School of Medicine, Seoul, Korea.
early dropout rate due to AEs was found to be higher in the Sang-Heon Lee, Department of Rheumatology, Konkuk Uni-
misoprostol group (27.4%, 1,210/4,404 subjects) than the versity School of Medicine, Seoul, Korea.
placebo group (20.1%, 896/4,439 subjects) (p<0.001).21 Hyun Ok Kim, Department of Rheumatology, Gyeongsang
Consequently, rebamipide can be safely used in clinical National University School of Medicine, Jinju, Korea.
practice, even when administered with NSAIDs for 12 weeks.
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11. Iijima K, Ichikawa T, Okada S, et al. Rebamipide, a cytoprotective drug, increases gastric mucus secretion in human: evaluations with
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13. Kim HK, Kim JI, Kim JK, et al. Preventive effects of rebamip- ide on NSAID-induced gastric mucosal injury and reduction of gastric
mucosal blood flow in healthy volunteers. Dig Dis Sci 2007;52:1776-1782.
14. Naito Y, Yoshikawa T, Iinuma S, et al. Rebamipide protects
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 382

AYUE ZONE PRATITIS

PPDS BEDAH UMUM

UNIVERSITAS MULAWARMAN/
GENAP 2022

CRITICAL APPRAISAL

PICO Analysis

PICO

Population Pasien yang mendapatkan obat OAINS untuk keluhan nyeri sendi (Osteoartritis,
Populasi yang diteliti Reumatoid Artritis, Trauma muskuloskletal)

Intervention Rebamipide 100 mg tiga kali sehari selama 12 minggu

Intervensi yang diberikan

Comparison Misoprostol 200 mcg misoprostol tiga kali sehari selama 12 minggu
Kelompok perbandingan yang diteliti

Outcome Kejadian ulkus gaster, perforasi, perdarahan gaster

Hasil penelitian

Critical Appraisal Checklist for RCT

1. Was true randomization used for assignment of participants to treatment groups?
2. Was allocation to treatment groups concealed?
3. Were treatment groups similar at the baseline?
4. Were participants blind to treatment assignment?
1. Was true 5. Were those delivering treatment blind to treatment assignment? randomization
6. Were outcomes assessors blind to treatment assignment?
used for 7. Were treatment groups treated identically other than the intervention of interest?
assignment of
participants to 8. Was follow up complete and if not, were differences between groups in terms of treatment
their follow up adequately described and analyzed?
groups? 9. Were participants analyzed in the groups to which they were randomized?
10. Were outcomes measured in the same way for treatment groups?
(Apakah benar 11. Were outcomes measured in a reliable way? pengacakan
digunakan 12. Was appropriate statistical analysis used? untuk
13. Was the trial design appropriate, and any deviations from the standard RCT design
penugasan (individual randomization, parallel groups) accounted for in the conduct and analysis of peserta ke
the trial?
kelompok perlakuan?)

Ya, Pada penelitian

ini yang menggunakan
 383
teknik double blind, double dummy, randomized, multicenter, dan uji klinis perbandingan paralel.
Dimana subyek yang setuju untuk berpartisipasi dan tergolong kriteria inklusi secara acak ditugaskan
dalam kelompok perlakuan (rebamipide) dalam kelompok kontrol (misoprostol). Untuk perawatan
kelompok perlakuan menerima 100 mg rebamipide tiga kali sehari, dan kelompok kontrol menerima
200 mcg misoprostol tiga kali sehari selama 12 minggu. Titik akhir utama dari analisis adalah tingkat
terjadinya ulkus lambung, sebagaimana ditentukan oleh endoskopi setelah 12 minggu terapi.

2. Was allocation to groups concealed?

(Apakah alokasi untuk kelompok disembunyikan?)

Pada penelitian ini tidak disebutkan penyembunyian alokasi (allocation concealment)

3. Were treatment groups similar at the baseline?

(Apakah kelompok perlakuan serupa pada awal penelitian?)

Ya, dimana pada penelitian ini disebutkan bahwa karakteristik dasar subyek sama antar
kelompok dimana ditandai dengan pemberian regumen obat jenis OAINS (aceclofenac 100 mg dua
kali sehari, meloxicam 15 mg sekali sehari, atau nabumetone 1.000 mg sekali sehari) yang dibuktikan
nilai p value > 0,05. Begitu juga pada gambaran karakteristik demografi (umur, jenis kelamin, riwayat
perokok, faktor resiko terjadi ulkus, grading screening endoscopy atau skor Lanza) yang dibuktikan
dengan nilai p value > 0,05 yang artinya masing – masing kelompok diberi perlakuan secara equally
atau sama di awal penelitian.

4. Were participants blind to treatment assignment?

(Apakah peserta buta terhadap tugas pengobatan?)

Ya, dalam penelitian ini disebutkan bahwa pada penelitian ini menggunakan teknik double
blind (pembutaan ganda),, double dummy, randomized yang artinya pasien tidak mengetahui obat apa
yang diberikan kepada pasien tersebut. Namun pada penelitian ini tidak disebutkan atau dijelaskan
secara detail terkait prosedur penyamaran atau prosedur yang mencegah peserta mengetahui kelompok
mana mereka dialokasikan yang gunanya untuk membutakan peserta digunakan untuk meminimalkan
risiko ini.

5. Were those delivering treatment blind to treatment assignment?

(Apakah mereka yang memberikan pengobatan buta terhadap penugasan pengobatan?)
 384

Ya, dalam penelitian ini disebutkan bahwa pada penelitian ini menggunakan teknik double
blind (pembutaan ganda), double dummy, randomized yang artinya peneliti tidak mengetahui obat apa
yang diberikan kepada pasien. Namun pada penelitian ini tidak disebutkan atau dijelaskan secara detail
terkait prosedur penyamaran.

6. Were outcomes assessors blind to treatment assignment?

(Apakah penilai hasil buta terhadap tugas pengobatan?)

Ya, dalam penelitian ini disebutkan bahwa pada penelitian ini menggunakan teknik double
blind (pembutaan ganda), double dummy, randomized yang artinya peneliti dan yang diteliti sama-
sama tidak mengetahui obat apa yang diberikan kepada pasien, sehingga penilai hasil yang dibutakan
digunakan untuk meminimalkan risiko dan tidak ada yang mengintervensi.

7. Were treatment groups treated identically other than the intervention of interest?
(Apakah kelompok perlakuan diperlakukan secara identik selain dari intervensi yang diminati?)

Ya, Pada kelompok-kelompok yanng diteliti diperlakukan secara sama atau seimbang mulai
dari lama waktu perlakuan yaitu 12 minggu, lalu dosis obat yang diberikan sama – sama sebanyak 3
kali sehari, pemantauan selama 12 minggu, dan setelah itu sama – sama dilakukan endoskopi evaluasi.

8. Was follow up complete and if not, were differences between groups in terms of their follow up
adequately described and analyzed?
(Apakah tindak lanjut selesai dan tidak, ada perbedaan antara kelompok dalam hal mereka tindak
lanjut dijelaskan dan dianalisis secara memadai?)

Ya, Pada penelitian ini dilakukan follow up sampai selesai yaitu selama 12 minggu (yaitu, sejak
saat alokasi acak hingga akhir waktu uji coba), sehingga untuk terjadinya bias pada penelitian ini
sangat kecil.

9. Were participants analyzed in the groups to which they were randomized?

(Apakah peserta dianalisis dalam kelompok yang diacak?)
 385

Ya, analisis dengan ITT (Intention to Treat Population) yang artinya mengikut sertakan semua
subyek penelitian walaupun subyek tersebut drop out dari penelitian. Analisis utama ditetapkan untuk
khasiat dalam penelitian ini adalah analisis niat untuk mengobati (ITT) karena perangkat analisis PP
dianggap kurang valid dari analisis ITT ditetapkan karena perbedaan yang signifikan dalam tingkat
penarikan antara kedua kelompok.

10. Were outcomes measured in the same way for treatment groups?
(Apakah hasil diukur dengan cara yang sama untuk kelompok perlakuan?)

Ya, Pada penelitian ini hasil yang didapatkan diukur dengan cara yang sama. Dimana waktu
pengukuran yang sama – sama dilakukan selama 12 minggu, dan sama – sama diberi perlakuan dan
dosis obat perhari yang sama.

11. Were outcomes measured in a reliable way?

(Apakah hasil diukur dengan cara yang dapat diandalkan?)

Ya, Untuk angka kejadian tukak lambung dan angka kegagalan terapi, frekuensi dan persentase
terjadinya tukak lambung dan kegagalan terapi diperoleh, dan perbandingan dari tingkat mereka antara
kelompok dilakukan dengan menggunakan chi-kuadrat tes. Untuk persentase subjek yang mengalami
efek samping peristiwa (AE) lebih dari sekali, interval kepercayaan 95%. diperoleh dan perbedaan
antar kelompok dibandingkan dengan menggunakan uji chi-square atau uji eksak Fisher. SAS versi 9.1
(SAS Institute, Cary, NC, USA) digunakan untuk melakukan statistik analisis.

12. Was appropriate statistical analysis used?

(Apakah analisis statistik yang tepat digunakan?)

Analisis statistik yang tepat digunakan pada penelitian ini yaitu chi-square test or Fisher exact
test. SAS version 9.1 (SAS Institute, Cary, NC, USA)

13. Was the trial design appropriate for the topic, and any deviations from the standard RCT
design accounted for in the conduct and analysis?
 386
(Apakah desain percobaan sesuai dengan topik, dan apakah ada penyimpangan dari RCT standar
desain diperhitungkan dalam melakukan dan analisis?)

Ya, desain percobaan sudah sesuai dengan topik, dan tidak didapatkan adanya penyimpangan
RCT standar dalam melakukann analisis.