Comparison of Helicobacter pylori eradication rates between 7 and 14 days of tailored therapy according to clarithromycin resistance test: A randomized, multicenter, non‐inferiority study

Recently, a simple tailored therapy based on clarithromycin resistance has been implemented as Helicobacter pylori (H. pylori) eradication therapy. Nonetheless, despite the tailored therapy and frequent adverse events, studies on treatment period are lacking. This study aimed to compare the H. pylori eradication rates of 7‐day and 14‐day tailored therapy regimens according to clarithromycin resistance.


| INTRODUC TI ON
Helicobacter pylori (H.pylori) infection substantially contributes to gastrointestinal disorders, including gastritis, peptic ulcers, and gastric cancer. 1 The occurrence of diseases linked to H. pylori infection poses a considerable health risk, emphasizing the imperative need for effective eradication treatments.H. pylori-associated gastrointestinal disorders underscore the importance of promptly addressing this bacterial infection. 2e success of H. pylori eradication treatment hinges on factors such as compliance, adverse events, and antibiotic resistance. 3In order to improve eradication success, it is crucial to meticulously select appropriate antibiotics, minimize side effects, and ensure the completion of the entire course of medications by the patients.
Among several antibiotics used for H. pylori eradication, clarithromycin resistance is an important factor that leads to treatment failure. 4cent guidelines advocate routine H. pylori susceptibility testing using molecular techniques such as polymerase chain reaction (PCR) even before the initiation of first-line treatment. 5,6Considering that adverse events can escalate with treatment duration, determining the appropriate treatment duration is pivotal in improving the eradication success and mitigating additional antibiotic resistance. 7In response to these considerations, tailored therapy based on point mutations of clarithromycin resistance in the 23S rRNA gene of H. pylori has been implemented as an eradication strategy to enhance efficacy and minimize drug side effects. 8,9Nonetheless, with respect to tailored therapy based on antibiotic susceptibility testing, evidence for the optimal duration or shortening the treatment duration remains insufficient.
The present study aimed to compare the H. pylori eradication rates between 7-day and 14-day tailored therapy regimens according to clarithromycin resistance.This exploration would provide valuable insights into the optimization of treatment duration and improvement of overall treatment success, considering the multifaceted nature of H. pylori infections and the complexities involved in achieving successful eradication.

| Study population and design
This multicenter, prospective, randomized, non-inferiority trial was conducted on patients with H. pylori infection who underwent endos- Eligible patients were randomly assigned to either a 7-day or 14-day regimen group using a randomization table stratified by H. pylori clarithromycin resistance in a computer.The allocation ratio between the groups was 1:1.After assignment, both the participants and physicians were informed about the eradication regimens and were no longer blinded.

| Diagnosis of H. pylori clarithromycin resistance
Two biopsy specimens were obtained from the patients' antrum and corpus during endoscopy.For the diagnosis of H. pylori infection, DPO-PCR was performed on the DNA extracted from gastric biopsy specimens using the Seeplex H. pylori-ClaR ACE Detection kit (Seegene Inc., Seoul, Korea).PCR was carried out to amplify a portion of the 23S rRNA gene to identify clarithromycin resistanceassociated mutations-namely, A2142G and/or A2143G.

| Eradication regimens
After dividing all patients into the 7-day-and 14-day regimen groups, the final drug was selected according to clarithromycin resistance based on DNA PCR results.For the 7-day regimen group, standard triple therapy (STT) (20 mg rabeprazole, 1.0 g amoxicillin, and 500 mg clarithromycin) was administered twice daily if the point mutation was negative, and bismuth quadruple therapy (BQT) (20 mg rabeprazole twice a day, 500 mg metronidazole thrice a day, 120 mg bismuth four times a day, and 500 mg tetracycline four times a day) was administered four times a day if the point mutation was positive.
For the 14-day regimen group, the drugs were the same as those mentioned above and administered for an additional week.
For patients in whom eradication treatment failed, salvage therapy was administered as follows: when the primary treatment failed in patients without point mutations, BQT was administered for one or 2 weeks according to the assigned group.If this eradication failed again, secondary salvage treatment (levofloxacin-based triple therapy [20 mg rabeprazole, 1.0 g amoxicillin twice daily, and 500 mg levofloxacin once daily] for 2 weeks) was initiated.If eradication failed after treatment with BQT in the group with a point mutation, the patients immediately proceeded to secondary salvage treatment.

| Assessment of compliance and treatment-related adverse events
All patients were instructed on how to report any adverse events and ensure drug compliance.The compliance level was determined based on the intake of prescribed medications.Noncompliance was defined as the intake of <80% of the total medications based on the number of remaining pills.Adverse events were graded as mild, moderate, or severe.Mild adverse reactions were defined as having more than 80% drug compliance and experiencing side effects that did not disrupt daily activities.
Moderate adverse reactions were defined as having less than 80% drug compliance and experiencing side effects that affected daily activities.
Severe adverse reactions were defined as having less than 50% drug compliance or experiencing side effects that limited daily activities.

| Outcomes and confirmation of H. pylori eradication
In this study, the primary outcome was the difference in eradication success rates between the 7-day and 14-day regimen groups, whereas the secondary outcome was the differences in patient compliance and adverse events related to eradication treatment during each treatment duration.A subgroup analysis was conducted to confirm the differences in eradication success rates according to the treatment duration and the presence or absence of 23S rRNA point mutations.The success of H. pylori eradication was evaluated at least 4 weeks after treatment using the 13 C-urea breath test (UBiT-IR300; Otsuka Electronics Co. Ltd., Tokyo, Japan).All patients fasted for 4 h before swallowing a 100 mg tablet of 13 C-urea (UBiTkit; Otsuka Pharmaceutical Co. Ltd., Tokyo, Japan) with 100 mL of water.Two breath samples were obtained before and at 20 min after swallowing the tablet.A 13 CO2 level below 2.5% was regarded as a successful eradication of H. pylori. 10

| Sample size estimation and statistical analysis
This study was designed as a non-inferiority trial, with the sample size estimated based on the eradication rate reported in previous studies.
The eradication rate of the 14-day tailored therapy was approximately 86.5% to 94.6% as first-line therapy, 11,12 while the eradication rate of the seven-day tailored therapy was noted as 90.8% to 91.8% (resulting from mostly seven-day regimen) in the previous studies. 13,14Assuming an about 91% eradication rate in the 14-day tailored therapy group and an about 91% eradication rate in the 7-day therapy group, as well as a non-inferiority margin of −10%, power of 80%, and alpha of 0.025, at least 141 patients per each treatment group would be required to demonstrate non-inferiority of two groups based on the H. pylori eradication rate. 15Considering a 10% dropout rate, at least 314 participants (157 participants per group) were expected to be recruited for the study.The H. pylori eradication rate in each group was evaluated using intention-to-treat (ITT) and per-protocol (PP) analyses.The ITT analysis included all enrolled participants after excluding patients who met the exclusion criteria, whereas the PP analysis excluded patients who were lost to follow-up or were noncompliant (consumed <80% of prescribed medications).Comparative non-inferiority of the two groups was assessed through hypothesis testing (one-sided μ-test) and derivation of a two-sided 95% confidence interval (CI).If the p-value for non-inferiority was <0.025 and the lower bound of 95% CI for the difference exceeded −10%, the non-inferiority of the 7-day eradication group versus the 14-day eradication group was concluded.Betweengroup differences were evaluated using Student's t-test for continuous variables and the chi-square test or Fisher's exact test for categorical variables, as appropriate.All p-values were two-sided, except for those in the non-inferiority test.Statistical analyses were performed using SPSS version 26.0 for Windows (IBM Corp., Armonk, NY, USA), with statistical significance set at a p-value of <0.05.

| Patient characteristics
Figure 1 illustrates the patient flow throughout the study.A total of 314 patients (190 males and 124 females) were enrolled in this study and randomly assigned to either the 7-day or 14-day regimen group.A2142G and/or A2143G point mutations were identified through DPO-PCR in 90 patients (28.7%) who were deemed to be infected with clarithromycinresistant H. pylori.The two groups showed no significant differences with respect to baseline clinical characteristics, including age, sex, presence of hypertension and/or diabetes mellitus, history of smoking and alcohol consumption, and reason for eradication therapy (Table 1).
Eradication success was not evaluated in 31 patients (7-day regimen group, n = 15; 14-day regimen group, n = 16) who were lost to follow-up after eradication.Two patients in the 7-day regimen group (STT, n = 1; BQT, n = 1) and three patients in the 14-day regimen group (STT, n = 2; BQT, n = 1) failed to take more than 80% of the total medications.Hence, 314 patients (157 patients per group) were included in the ITT analysis, whereas 278 patients (140 patients in the 7-day regimen group and 138 patients in the 14-day regimen group) were included in the PP analysis (Figure 1).
The eradication rates did not significantly differ between the two groups (p > 0.99 and 0.851 in the ITT and PP analyses, respectively; Figure 2).

| Non-inferiority of eradication rates between the two groups
The 7-day regimen therapy fulfilled the criteria for non-inferiority to the 14-day regimen therapy in the ITT and PP analyses.The null hypothesis for the inferiority of the 7-day regimen therapy to the 14day regimen therapy was rejected (one-sided p = 0.015 and 0.011 in the ITT and PP analyses, respectively; Table 2).Moreover, the lower bound of 95% CI for the difference in eradication rates from the 14day regimen group was greater than the prespecified non-inferiority margin of −10%.Therefore, the 7-day regimen group was not inferior to the 14-day regimen group because the lower bound of the same CI was less than zero.

| Subgroup analysis of eradication rates
In the subgroup of patients infected with H. pylori without 23S rRNA point mutations, the eradication rates were 80.4% and 81.3% in the 7-day and 14-day regimen groups, respectively, in the ITT analysis and were 90.0% and 90.1% in the 7-day and 14-day regimen groups, respectively, in the PP analysis.No statistically significant differences were found for patients infected with H. pylori harboring mutations (p > 0.99 in the ITT and PP analyses; Figure 3A).
On the ITT analysis, the eradication rates of H. pylori-infected patients with A2142G and/or A2143G point mutations were 73.3% in the 7-day regimen group and 71.1% in the 14-day regimen group, with no significant difference between the two groups (p > 0.99).
Furthermore, on the PP analysis, the eradication rates were 82.5% in the 7-day regimen group and 86.5% in the 14-day regimen group.Although there was a numerical difference of approximately 4%, the two groups showed no statistically significant difference (p = 0.757; Figure 3B).

| Salvage therapy
Out of 32 patients who did not respond to the first eradication treatment in both groups, seven decided not to undergo further treatment.The remaining 25 patients received re-treatment using the protocol's salvage therapy.Among them, 24 patients were successfully treated (Table 3).However, despite having no 23S rRNA point mutation, one patient with H. pylori infection failed to achieve eradication even with STT, BQT, and levofloxacin-based triple therapy.

| Adverse events and compliance rates
Adverse events, such as bitter taste, nausea, vomiting, headache, skin rashes, abdominal pain, and dizziness, occurred in 33 (21.0%) out of 157 patients in the 7-day regimen group and 34 (21.7%)out of 157 patients in the 14-day regimen group (p = 0.967).Among these 67 patients, nine in the 7-day regimen group and six in the 14-day regimen group (four triple therapy cases) reported a bitter taste.The most common adverse event was nausea/vomiting (13 patients per group; Table 4).
In the additional analysis of the frequency of adverse events according to the STT and BQT regimens, the incidence rate in the BQT group was statistically significantly higher at 33.3% (30/90) compared to 16.5% (37/224) in the STT group (p = 0.002).However, severe adverse events were 1 case in the STT group and 2 cases in the BQT group, which did not show a statistically significant difference (p = 0.199).Additionally, while there was a considerable incidence rate of adverse events in the BQT group, there was no difference between the 7-day (17/45) and 14-day (13/45) regimens (p = 0.503) within the BQT group.
The compliance rates were 98.6% (140/142) and 97.9% (138/141) in the 7-day and 14-day regimen groups, respectively.Only one patient in the 7-day regimen group and two patients in the 14-day regimen group were deemed to be noncompliant because their medication consumption was <80%.One patient in the 7-day regimen group stopped taking the medication owing to severe nausea/ vomiting and headaches, whereas two patients in the 14-day regimen group stopped taking the medication because of dizziness.
However, after discontinuing the eradication medication and receiving symptom-based treatment, all patients recovered without hospitalization.The other two patients (one in the 7-day regimen group and one in the 14-day regimen group) did not complete the medication because of indifference.

| DISCUSS ION
In clinical practice, eradication therapy usually involves a combination of acid suppressants and various antibiotics administered over one to 2 weeks.Nevertheless, it is often difficult for patients to continuously take antibiotics for 2 weeks, 16 and this criterion was not established through the confirmation and progression of antibiotic resistance, but rather through empirical treatment in previous studies.A Korean national survey recently revealed that the resistance rate of H. pylori to any antibiotic agent had increased by more than 50%, 9 suggesting that future H. pylori eradication therapies should focus on minimizing the occurrence of antibiotic resistance.
Accordingly, tailored therapy using the DPO-PCR method, which is widely used in clinical practice, has been recommended both domestically and internationally. 5,6However, despite numerous studies on the usefulness of tailored therapy using the DPO-PCR method, research establishing the treatment duration for H. pylori eradication therapy remains scant.Therefore, this study was initiated under the assumption that if the presence or absence of clarithromycin resistance is known, the duration of drug administration can be shortened Abbreviations: CI, confidence interval; ITT, intention-to-treat; PP, per-protocol.
a Two-sided p-values for the comparison of differences between the 7-day and 14-day groups.
b One-sided p-values for the comparison of non-inferiority between the 7-day and 14-day groups.
F I G U R E 2 Overall eradication rates according to 7-day and 14day regimens in the intention-to-treat (ITT) and per-protocol (PP) analyses.
without decreasing the eradication success rate.This study aimed to verify the difference in eradication success rates between 7-day and 14-day regimens with a simple tailored therapy for H. pylori using the DPO-PCR method.The results of this non-inferiority trial suggest that if H. pylori eradication therapy is determined based on the presence or absence of clarithromycin resistance, a 1-week treatment can be as effective as a 2-week treatment.
In this study, irrespective of the presence or absence of resistance, the overall 7-day and 14-day eradication rates were 87.9% and 89.1%, respectively.The difference in eradication rates over this period did not show any statistical significance and was confirmed by the non-inferiority test.In a previous prospective randomized trial, Kim et al. compared the 7-day and 14-day regimens regardless of the resistance test and reported eradication success rates of 78.5% and 78.6%, respectively, in the PP analysis, showing that the treatment period had no effect. 17Moreover, recent retrospective studies have consistently reported no significant difference in eradication success rates between 7-day and 14-day therapies.For instance, Na et al. found no statistical difference between the 7-day therapy success rate of 90.3% (89.6% for the STT and 91.4% for the BQT in the PP analysis) and 14-day therapy success rate of 88.4% (87.2% for the STT and 90.3% for the BQT in the PP analysis). 18Similarly, Bae et al.
reported that 7-day and 14-day STT resulted in eradication rates of 89.7% and 93.3%, respectively, whereas 7-day and 14-day BQT led to eradication rates of 88.8% and 80.0%, respectively, with the 14day therapies not demonstrating a significantly superior eradication effect compared to the 7-day therapies. 19Our prospective study is expected to provide a foundation for recommending further evidence based on the aforementioned retrospective studies.
We also conducted separate analyses based on the presence or absence of clarithromycin resistance.In this study, the rate TA B L E 3 Summary of salvage therapy.

TA B L E 4
Adverse events and compliance in the treatment groups.  of clarithromycin resistance was found to be 28.7%.In a national susceptibility study in Korea, the resistance rate of clarithromycin was reported to be 17.8%. 9Additionally, a study tracking resistance rates over the past 16 years reported an increasing trend in clarithromycin resistance, ranging from 21.2% to 45.9%. 20There have also been reports of 37.7% and 43.1% resistance rates in retrospective studies, 18,21 indicating regional and methodological differences in clarithromycin resistance among H. pylori strains.However, our previous study also showed a resistance rate of 28.6%, suggesting that the resistance rate in this region is approximately 25%-30%. 12rthermore, recent European guidelines consider regions with a clarithromycin resistance rate of 15% or higher as high resistance frequency regions, a criterion that applies to all the rates above. 6garding the treatment of clarithromycin-resistant H. pylori, recent Korean guidelines recommend standard three-drug therapy for 7 days if the clarithromycin test is negative.In a previous study conducted by this co-investigator, 13 in which a total of 366 patients were analyzed, the eradication success rates in the PP analysis were 90.8% for the 7-day STT regimen and 90.4% for the 14-day STT regimen.As mentioned in the guidelines, a 7-day treatment is sufficient and is becoming the standard treatment for H. pylori that is not resistant to clarithromycin.Similar to the above study, our results showed no difference between 7-day and 14-day regimens, with clarithromycin resistance-negative cases at 90.0% and 90.1%, respectively.
However, in cases of clarithromycin resistance, guidelines recommend proton pump inhibitor, amoxicillin, metronidazole (PAM) 7-day therapy or immediate implementation of the BQT regimen. 5rthermore, the guidelines specify 10-14 days for the BQT regimen.However, the duration of the BQT regimen is based on data for second-line therapy when the initial therapy has failed, and there is no evidence for initial therapy in cases of clarithromycin resistance.
The meta-analysis that separately analyzed the results of BQT, involving four studies for 7-day therapy and five studies for 10-to 14-day therapy, was based on studies targeting patients who failed first-line therapy, as mentioned earlier. 5These studies showed empirical treatment results without confirming clarithromycin resistance through methods such as DPO-PCR testing during the study.
Therefore, based solely on this evidence, there is insufficient evidence to recommend 10-14 days of treatment in all clarithromycinresistant cases.
Additionally, although PAM therapy is recommended as a firstline treatment for clarithromycin resistant cases, 5 the efficacy of PAM therapy was 70.5% by PP analysis in a study conducted at our institution, indicating that it may be challenging to apply it as the primary eradication therapy. 11Especially considering the distribution of antibiotic resistance conducted by nationwide antibiotic resistance study, where strains with two or more resistances account for more than 20%, 9 the low efficacy of PAM therapy can be interpreted as being due to strains with simultaneous resistance to clarithromycin and metronidazole, among others.Therefore, in cases of clarithromycin resistance, it is beneficial to prioritize BQT over PAM therapy to achieve higher eradication success rates.However, in the case of BQT, problems with compliance arise owing to the number and frequency of medications taken, and subsequent studies and this study have proven that even a 7-day therapy is effective.Two retrospective studies on 7-day and 14-day BQT showed no significant difference in efficacy, with rates of 90.3% and 100% for 7 days and 91.4% and 90.3% for 14 days, respectively. 18,19Similarly, in this study, when comparing the results of BQT according to duration of strains with clarithromycin resistance, there was no statistically significant difference (82.5% and 86.5% in PP analysis), indicating consistent results between retrospective and prospective studies.
The lack of a difference between the 7-day and 14-day therapies could be primarily attributed to the tailored treatment approach.
However, we also noted the possibility that the results were influenced by factors such as body mass index (BMI) and age.Previous studies reported a significant decrease in H. pylori eradication rates in overweight or obese patients. 22,23However, in this study, there was no difference in BMI between the 7-day and 14-day regimens in the successful and failed eradication groups.Additionally, given that the average BMI in both groups was lower than 25 (24.42 ± 3.63) kg/m 2 , the correlation between BMI and the success of eradication treatment was expected to be deficient in this study.A previous report indicated that the eradication failure rate was twice as high in people aged >70 years; nonetheless, the average age in this study was 60 years, and the effect of age was therefore believed to be small. 24Additionally, with respect to side effects and compliance, we considered that the 14-day regimen would have more significant side effects or lower compliance; however, there was no significant difference between the 7-day and 14-day groups.A previous retrospective study also showed no difference between the two groups 18,19 ; therefore, the effect of duration on adverse events or compliance was likely to be small.
In the case of BQT in resistant strains, the eradication success rate was not above 90%, even in the PP analysis.This study did not perform H. pylori culture or minimum inhibitory concentration tests for other antibiotics, such as amoxicillin, tetracycline, and metronidazole, which may have affected the eradication rates.Therefore, multidrug-resistant strains may have contributed to the low eradication success rate in patients receiving BQT, and the lack of confirmation of resistance to other antibiotics may be considered a limitation.Hence, it is necessary for future studies to compare various treatment options specifically for patients with clarithromycin resistance.Additionally, it is necessary to confirm the overall antibiotic resistance in patients who fail eradication after 7-day therapy to determine the frequency of multiple resistances.However, in a meta-analysis study, the eradication success rate of BQT as the firstline treatment was 82.1% in the ITT analysis and 88.8% in the PP analysis. 25In another meta-analysis, the overall efficacy of BQT was confirmed to be 87%, ensuring that the success rate of BQT eradication treatment does not exceed 90%, similar to this study. 26Of course, this study did not show a statistical difference.Still, it showed a 4% difference in the eradication success rate of BQT groups, so if a large-scale study is conducted, the eradication success rate could be significantly different, as it has been reported that resistance to metronidazole is overcome as the administration period increases. 27wever, considering the simple treatment algorithm, side effects, and compliance, a unified 7-day regimen can be a sufficient alternative in selecting treatment drugs through DPO-PCR.
Despite being a prospective, multicenter, randomized, noninferiority trial, this study has several limitations.First, the limitations of DPO-based PCR testing are considered the most substantial.The product used can only detect A2142G and A2143G point mutations, and other clinically significant point mutations possibly exist, including A2142C, A2143C, and A2144G, which are not currently detected by DPO-PCR. 28However, these mutations alone are associated with less than 5% of clarithromycin-resistant H. pylori isolates in Korea. 28ditionally, DPO-based multiplex PCR can determine only the presence of clarithromycin resistance, and we did not attempt H. pylori cultures for other antibiotic susceptibility tests.Therefore, we could not identify resistance to other antibiotics or overlapping resistance between clarithromycin and other antibiotics.Nevertheless, DPO-PCR, which is the most convenient and easy method to proceed with tailored treatment in clinical practice, is a reasonable and efficient diagnostic and treatment decision-making method.Second, this study expected a 10% dropout rate, but follow-up loss was greater than expected.Therefore, the actual eradication success rate might have been underestimated because of these factors.In the absence of any considerable clinical inconvenience, there are many cases in which patients do not visit the actual treatment site to check whether the eradication has been successful after the eradication treatment.
One study reported that the eradication success rate was increased by a semi-automated intensive follow-up system and suggested that reducing the follow-up loss was an essential factor in future research on eradication rates. 29Third, the diversity of H. pylori strains is a factor, and heterogeneity of H. pylori within a single patient might result in treatment failure even after BQT for the presence of 23S rRNA point mutations. 30Therefore, we can consider the coexistence of clarithromycin-resistant and clarithromycin-sensitive strains, and there is a limitation in that only the strains found in the tissue sample are considered.Despite these limitations, this multicenter prospective study has clinical significance in that it demonstrated that even if only the clarithromycin DPO-PCR resistance test, which is the most easily performed test clinically, was used, the eradication success rate was not inferior when a 7-day tailored eradication therapy was implemented.

| CON CLUS ION
This study revealed that the 7-day triple or quadruple therapy based on clarithromycin resistance was non-inferior to the 14-day therapy in terms of eradication rates.The eradication rates, adverse events, and patient compliance did not significantly differ between the 7day and 14-day regimens in the STT and BQT treatment cohorts.
This study suggests that the 7-day tailored therapy is as effective as the 14-day therapy in eradicating H. pylori following simple DPO-PCR clarithromycin susceptibility testing.
copy at six tertiary care hospitals (Kosin University Gospel Hospital, Busan Paik Hospital, Haeundae Paik Hospital, Dong-A University Hospital, Pusan National University Hospital, and Pusan National University Yangsan Hospital) located in Busan and Geyongnam-do, South Korea, from August 2021 to December 2022.Patients aged 18-80 years who tested positive for H. pylori on various tests, including histological, rapid urease, serological, and urea breath tests, and also underwent dual-priming oligonucleotide-based PCR (DPO-PCR) for clarithromycin resistance were eligible to participate in the trial.The exclusion criteria were as follows: a history of H. pylori eradication; use of proton pump inhibitors or antibiotics for >3 days in the past month; having undergone partial gastrectomy; severe liver, kidney, or cardiopulmonary dysfunction; and non-provision of patient consent.
This study was approved by the ethics committees of Kosin University Gospel Hospital (KUGH 2021-07-022), Busan Paik Hospital (2021-08-036), Haeundae Paik Hospital (HPIRB 2021-08-032-002), Dong-A University Hospital (DAUHIRB-21-225), Pusan National University Hospital (2111-034-108), and Pusan National University Yangsan Hospital (05-2021-232) and was conducted in accordance with the ethical standards set by the responsible committees on human experimentation, both at the institutional and national levels, and with the 1964 Helsinki Declaration and its subsequent revisions.This randomized trial was registered at the Clinical Research Information Service of the Korea National Institute of Health (KCT0006574).

F I G U R E 1
Flow diagram of this study.BQT, bismuth quadruple therapy; DPO-PCR, dual-priming oligonucleotide-based polymerase chain reaction; ITT, intentionto-treat; PP, per-protocol; STT, standard tripe therapy; UBT, 13 C-urea breath test.TA B L E 1 Baseline characteristics of the patients.

F I G U R E 3
Eradication rates of the subgroups according to clarithromycin resistance.(A) Absence and (B) presence of point mutation in the intention-to-treat (ITT) and per-protocol (PP) analyses.BQT, bismuth quadruple therapy; STT, standard tripe therapy.

day group (n = 157) 14-day group (n = 157) Difference from the 14-day group (adjusted 95% CI for difference) p-value for difference a p-value for non-inferiority b
TA B L E 2 Eradication rate of each group in the ITT and PP analyses.7-