Original Article

Cent Asian J Med Sci. 2016 Nov;2(2): 169-175.

Randomized Controlled Trial Comparing Standard

Triple and Sequential Regimens for Helicobacter
pylori Eradication
Byambajav Tsogt-Ochir1, Oyuntsetseg Khasag1, Bira Namdag1, Erdenetsogt Dungubat2, Choijamts Gotov3,
Sarantuya Tserenchimed4, Enkhtsetseg Altangerel5
1
Department of Gastroenterology, School of Medicine, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia; 2Department of Pathology, School of
Medicine, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia; 3Otoch Manramba University of Mongolia, Ulaanbaatar, Mongolia; 4Department
of Internal Medicine, United Family Intermed Hospital, Ulaanbaatar, Mongolia; 5Department of Laboratory, General Hospital of Defense and Law Enforcement,
Ulaanbaatar Mongolia

Submitted: August 1, 2016 Objectives: The aim of this study was to compare effectiveness of sequential therapy to the
Revised: September 4, 2016 standard triple therapy to eradicate Helicobacter pylori (H. pylori) in Mongolia. Methods:
Accepted: September 12, 2016
From September 2014 to February 2016, 140 patients with confirmed H. pylori infection (upper
gastrointestinal tract (GI) endoscopy, rapid urease test, histology, H. pylori stool antigen test
Corresponding Author (HpStAg)) randomly received 10 days standard triple therapy (20 mg pantoprazole, 1 g amoxicillin,
Byambajav Tsogt-Ochir, MD, MSc 500 mg clarithromycin, all twice daily for 10 days; STT group, n = 70), and sequential therapy
Department of Gastroenterology, (20 mg pantoprazole, 1 g amoxicillin twice daily for 5 days followed by 20 mg pantoprazole, 500
School of Medicine, Mongolian
mg clarithromycin, 500 mg metronidazole twice daily for 5 days; SQT group, n = 70). Successful
National University of Medical
Sciences, Ulaanbaatar 14210, eradication therapy for H. pylori infection was defined as a negative HpStAg test 4 weeks
Mongolia. after the end of eradication treatment. Results: The eradication rates by intention to treat
Tel: +976-8860-4486 (ITT) analysis were 71.4% (50/70) and 50% (35/70) in the STT and SQT groups, respectively
E-mail: byambajav@mnums.edu.mn (p = 0.033). The eradication rates by per-protocol (PP) analysis were 72.5% (50/69) and 51.5%
(35/68) in the STT and SQT groups, respectively (p = 0.018). The adverse event rates were 7.6%
This is an Open Access article distributed (5/70) and 18.6% (13/70) in the STT and SQT groups, respectively (p = 0.043). Conclusion: The
under the terms of the Creative Commons
Attribution Non-Commercial License (http:// eradication rate was significantly higher in the STT group compared with the SQT group. But the
creativecommons.org/licenses/bync/4.0/)
which permits unrestricted non-commercial
eradication efficacies of both STT and SQT for H. pylori infection in Mongolia are unacceptable.
use, distribution, and reproduction in any
medium, provided the original work is
properly cited. Copyright© 2016 Mongolian Keywords: Helicobacter pylori, Disease Eradication
National University of Medical Sciences

Introduction conditions [2]. The prevalence was 69-76% among adults [3,
4], 64% among adolescents, 65-100% among pediatric patients
Helicobacter pylori (H. pylori) infects approximately with gastric comorbidity [5], and 65.7% among patients
50% of the population worldwide [1]. As in other developing diagnosed with gastric ulcer [6].
countries, prevalence of H. pylori infection is reported to be Treatment of H. pylori infection is paramount for the
high in Mongolia, which is thought to be related to poor sanitary management of prevalent gastrointestinal disorders including

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 First Line Therapy of H. pylori

peptic ulcer disease and gastric cancer [7, 8]. Until now, the resection for adenoma or early gastric cancer; patients with
gold standard of H. pylori eradication regimen has been triple peptic ulcer disease and gastric cancer; the coexistence of
therapy, consisting of proton-pump inhibitor (PPI), amoxicillin serious concomitant illness (for example, decompensated
(AMX), clarithromycin (CAM) or metronidazole (MNZ) with a liver cirrhosis or kidney failure); alcohol abuse; pregnancy or
duration of 7-14 days [9, 10]. However, successful H. pylori lactation; Zollinger- Ellison syndrome; hematological disorders;
eradication rates with standard triple therapy (STT) have been and severe psychiatric or neurological disorders.
plummeting down due to increasing antibiotic resistance, having
declined to as low as below 70% in many countries [10, 11]. 2. Endoscopy and H. pylori detection
Therefore, many investigators have attempted to introduce All patients underwent upper GI endoscopy and gastric biopsy
regimens with higher efficacy for H. pylori eradication. Several was taken according to the updated Sydney System [17]. Before
strategies, including sequential therapy (SQT), concomitant enrollment, the status of H. pylori infection was determined by
therapy, and bismuth-containing quadruple therapy have a rapid urease test (Mon HP), histology (Eosin & Hematoxylin
therefore been proposed to increase the eradication rate [12-15]. staining and modified Giemsa staining), and H. pylori
SQT consists of a PPI and AMX for the first 5 days, followed by a stool antigen test (SD BIOLINE H. pylori Ag Enzyme-Linked
PPI plus CAM and MNZ for another 5 days. SQT has been shown Immunosorbent Assay (ELISA) kit, Korea). Patients with positive
to be more effective than STT in multiple randomized controlled results in at least two of these tests were eligible for enrollment.
trials and several meta-analyses, although several studies have H. pylori eradication was checked 6-8 weeks following therapy
also demonstrated conflicting results [14-16]. In Mongolia, no by using the SD BIOLINE H. pylori stool antigen test according
previous studies investigating the H. pylori eradication rate to the manufacturer’s directions.
exist. The purpose of this study was to compare the efficacy of
SQT to that of STT in eradicating H. pylori. 3. Randomization and treatment
Using a computer-generated number sequence, the eligible
Materials and Methods H. pylori-infected patients were randomly assigned to the
STT group (20 mg pantoprazole twice daily, 1 g amoxicillin
1. Subjects twice daily and 500 mg clarithromycin twice daily for 10
The open-labeled randomized trial was conducted at the days) and the SQT group (20 mg pantoprazole twice daily
Department of Gastroenterology, Mongolian National University and 1 g amoxicillin twice daily for 5 days, followed by 20 mg
of Medical Sciences in accordance with the principles of good pantoprazole twice daily, 500 mg clarithromycin twice daily
clinical practice according to the Declaration of Helsinki. Written and 500 mg metronidazole twice daily for 5 additional days).
informed consent was obtained from all participants, and the An independent research assistant generated the computerized
study protocol was approved by the Medical Committee of the random number sequence. PPIs were given a half-hour before
Mongolian National University of Medical Sciences (Ulaanbaatar, breakfast and dinner while antibiotics were given following
Mongolia). these meals. All patients received 2 weeks monotherapy with 20
Consecutive outpatients complaining of dyspeptic mg pantoprazole orally once daily following eradication therapy.
symptoms referred for upper GI endoscopy in the participating At the end of the treatment, both side effects and therapeutic
center in Ulaanbaatar, Mongolia were considered for compliance were assessed by personal interview.
recruitment to the study. Exclusion criteria were: age <18 years; The patients were informed of the common adverse events
previous H. pylori eradication therapy; consumption of PPI, from the study drugs before treatment and were asked to
histamine H2-receptor antagonists, bismuth and/or antibiotics, record these symptoms during treatment in provided diaries.
concomitant anticoagulant, nonsteroidal anti-inflammatory The adverse events were assessed according to a 4-point
drugs, or ketoconazole within the previous 4 weeks; patients scale system: 1 = none, 2 = mild (discomfort annoying but not
with allergic history to the medications used; previous surgery interfering with daily life), 3 = moderate (discomfort sufficient to
of the stomach, including endoscopic mucosal or submucosal interfere with daily life), and 4 = severe (discomfort resulting in

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Byambajav Tsogt-Ochir et al.

discontinuation of eradication therapy).

Compliance to treatment was considered excellent if the
patient took more than 90% of the medication, moderate if he/
she took 70-90% of the medication, and poor if the patient took
less than 70% of medications.

4. Statistical analysis
All statistical analyses were performed using the SPSS software
(version 20.0, SPSS Inc., Chicago, IL, USA). Comparisons
between patient groups were performed by using the t-test for
unpaired data and the Chi-squared test, as appropriate. The
eradication rates with their 95% confidence intervals (CI) were
calculated at both ‘intention-to-treat’ (ITT) and at ‘per protocol’
(PP) analyses. At ITT, all the enrolled patients were included,
Figure 1. Flowchart of patients in the study.
whilst at PP only compliant patients who had done HpStAg test
control were considered. Two-tailed p-values of less than 0.05 adverse effects. Therefore, the STT and SQT groups had 69 and
were considered statistically significant. 68 patients at PP analysis, respectively (Figure 1).
Compliance to treatment was excellent in 70 patients
Results (100%) of the STT group. In the SQT group, compliance to
treatment was excellent in 69 patients (98.5%) and poor in 1
A total of 140 H. pylori-infected patients were randomly patient (1.5%) (p = 0.78).
assigned to receive STT (n = 70) or SQT (n = 70). Patients Overall 5 (7.6%) and 13 (18.6%) patients in the STT and
were enrolled from September 2014 to February 2016. The SQT complained of side effects. The rate of side effects of the
data regarding the clinical characteristics of the patients are SQT was more than the STT (p = 0.04). One of the patients in the
summarized in Table 1. SQT group stopped the medication due to moderate vomiting
The subjects were all included in the ITT analysis for H. and severe nausea (Table 2).
pylori eradication. A total of 137 patients completed the study. According to ITT analysis, the eradication rates were 71.4%
One patient in the STT group and one patient in the SQT group and 50.0% in the STT and SQT groups, respectively (p = 0.033).
did not perform the control HpStAg ELISA test. One patient PP eradication rates were 72.5% and 51.5%, respectively (p =
in the SQT group had interrupted therapy because of severe 0.018, Table 3).

Table 1. Demographic and clinical characteristics of the enrolled patients

Characteristic Standard triple (n) Sequential (n) p-value

Total patients 70 70 -

Age (years) 38.7 ±15.6a 37.1 ±12.7a 0.64

Sex (male/female) 32/38 36/34 0.03

Smoking habit (yes/no) 11/59 13/57 0.82

Mean ±SD
a

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 First Line Therapy of H. pylori

Table 2. Adverse effects reported by the patients during treatment

Total number of patients (number of patients with mild/ moderate/ severe adverse
Adverse event events)
Standard triple (n = 70) Sequential (n = 70)
Nausea 0 (0/0/0) 6 (0/5/1)
Vomiting 0 (0/0/0) 4 (0/4/0)
Taste perversion 0 (0/0/0) 1 (0/2/0)
Diarrhea 1 (1/0/0) 1 (1/0/0)
Headache 1 (1/0/0) 0 (0/0/0)
Weakness 1 (1/0/0) 0 (0/0/0)
Skin rash 2 (2/0/0) 0 (0/0/0)
Other 0 (0/0/0) 1 (1/0/0)

Table 3. Major outcomes of the two therapies

Rate % (number/total number)
Outcome characteristic Standard triple therapy Sequential therapy p-value
(n = 70) (n = 70)
Eradication rate
Intention-to-treat 71.4 (50/70) 50.0 (35/70) 0.033
Per-protocol 72.5 (50/69) 51.5 (35/68) 0.018
Adverse events 7.6 (5/70) 18.6 (13/70) 0.043

Discussion introduce a regimen with an ideal H. pylori eradication rate. The

efficacy of STT is constantly decreasing worldwide recently. Two
If we consider H. pylori infection as an infectious disease, an meta-analyses including more than 53,000 patients have shown
ideal regimen would be the one that can eradicate H. pylori that the ITT cure rate is less than 80%. The most important
in more than 95% of cases, with less than 5% severe adverse explanation for the decrease in efficacy of the STT is the increase
effects. According to Graham’s classification, the efficacy of H. in H. pylori resistance to CAM [19-21].
pylori eradication regimens are considered as: A = excellent Sequential therapy was introduced as a novel therapeutic
(>95% PP eradication rate), B = good (90-95%), C = fair approach for H. pylori eradication by Zullo et al. in 2000 [22].
(85-89%), D = poor (81-84%), and F = unacceptable (≤80% This regimen is strictly an innovative approach rather than a
PP eradication rate) [18]. Therefore in our study, STT and SQT new strategy because it is based on a different combination of
regimens are classified as unacceptable regimens since the well-known drugs with an approved indication for H. pylori
eradication rates were 72.5% and 51.5%, respectively. The rate eradication. Meta-analyses conducted between 2007 and 2009,
of side effects is also an important issue. Incidence of adverse pooling mostly Italian evidence, confirmed the advantage of 10-
events was significantly higher in the SQT group compared with day SQT (cure rates >90%) over 7- or 10-day STT [15, 16, 23,
the STT group. 24]. In 2012 and 2013, two updated meta-analyses [25, 26] and
In Mongolia, no study had previously evaluated H. pylori two systematic reviews [27, 28], including studies on sequential
eradication rate. Therefore we cannot compare our results with the therapy from Asia, Europe, and Latin America, showed that the
studies in our country. But, in other countries, STT and SQT have mean eradication rates were dramatically lower (79-84%) than
mostly achieved poor and unacceptable H. pylori eradication those reported in the early Italian trials [15, 16, 23, 24]. These
rates. Since 1982, many investigations have been performed to poor results were confirmed in a global meta-analyses in 2013

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Byambajav Tsogt-Ochir et al.

when overall cure rates were found to be 84% [29]. The main limitations of this study were the fact that it was a
Some studies reported that CAM resistance decreased single-center study conducted on a small sample size, taken from
the efficacies of both SQT and STT, and that MNZ resistance a geographically limited population in Ulaanbaatar, Mongolia.
decreased the efficacy of SQT. In 2014, Zhou et al. reported no Furthermore, due to the nature of design of the study, treatment
significant difference between the eradication rates achieved was provided in an open-label manner with inadequate blinding.
with STT (66.4%) and SQT (72.1%) in either the ITT analysis or The strong point of this study is it being the first study that is
the PP analysis (72.7% and 76.5%, respectively) [30]. Patients evaluating the effect of STT and SQT on H. pylori eradication
in the SQT group with dual CAM-resistance and MNZ-resistance in Mongolia.
had a low eradication rate (43.9%) [30]. Therefore, the results In conclusion, the eradication rate was significantly
of our study may be partly due to the increasing prevalence of higher in the STT group compared with the SQT group. But
antibiotic resistance. the eradication efficacies of both STT and SQT for H. pylori
The most commonly used antibiotics in the first line infection in Mongolia were unacceptable. We suggest more
treatment of H. pylori in Mongolia include AMX, CAM, or evidence-based search and adoption of alternative standard
MNZ. The unpublished result from our group reported that the treatment regimens with good efficacy and safety. In the case of
antibiotic resistant strains of H. pylori were common in the failing first line therapy, an individual antibiotic resistance study-
Mongolian population (the resistance rate for AMX, CAM and led approach should be undertaken. Therapy duration is one of
MNZ were 17.6%, 37.4% and 72.5%, respectively). The current the factors that increased therapeutic efficacy. Future studies
recommendations from the Maastricht IV guidelines showed into alternative treatment should also include head-to-head
that in an area where the resistance rate of CAM is more than comparison of the same regimens with 10- and 14-day therapy
15-20%, it would be not recommended to use the STT [10]. durations to increase efficacy.
Therefore, regimens including CAM are also not suitable and
should not be chosen as first-line treatments in Mongolia. H. Conflict of Interest
pylori resistance to MNZ was very high (72.5%) in Mongolia.
This finding was consistent with other studies from developing The authors state no conflict of interest.
countries, possibly due to the common use of MNZ to treat
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