14-day Empirical Therapy Compared with 7-day Tailored Therapy for Helicobacter pylori Eradication in Korea: Results of the K-CREATE Phase II Study

Abstract

Purpose

There are ongoing debates regarding whether tailored therapy based on genotypic resistance can reduce treatment duration compared to empirical therapy. This study was a nationwide, multi-center, randomized trial conducted in Korea to compare the efficacy of 14-day empirical therapy with 7-day tailored therapy as a first-line treatment for Helicobacter pylori (H. pylori) eradication.

Materials and Methods

Patients were randomized to receive either 14-day empirical therapy or 7-day tailored therapy based on genotypic resistance. The empirical therapy consisted of a clarithromycin-based triple therapy (TT) regimen (twice-daily doses of pantoprazole 40 mg, amoxicillin 1 g, and clarithromycin 500 mg). Tailored therapy involved a 7-day TT in patients without genotypic resistance, while those with resistance received a 7-day bismuth quadruple therapy regimen (twice-daily doses of pantoprazole 40 mg, three-times-daily doses of metronidazole 500 mg, and four-times-daily doses of bismuth 300 mg and tetracycline 500 mg). Eradication rates were assessed using the ¹³C-urea breath test. The primary outcome was the eradication rate in each group.

Results

A total of 102 patients were enrolled. In the intention-to-treat analysis, eradication rates were 65.5% in the empirical therapy group and 82.9% in the tailored therapy group (p=0.076). In the per-protocol analysis, eradication rates were 67.9% and 86.7%, respectively (p=0.052). There was no significant difference in patient compliance between the two groups.

Conclusion

This study demonstrated that tailored therapy based on genotypic resistance may reduce treatment duration compared to empirical therapy in the eradication of H. pylori in Korea.

Graphical Abstract

INTRODUCTION

Recent guidelines recommend antibiotic susceptibility testing using molecular techniques or culture methods prior to prescribing clarithromycin-based regimens for Helicobacter pylori (H. pylori) eradication.¹,² Although clarithromycin remains a key antibiotic in the treatment of H. pylori infection, resistance rates have risen in many countries.³ Avoiding clarithromycin without confirmed resistance may result in the overuse of quadruple regimens, potentially leading to unnecessary antibiotic exposure, increased adverse events, and higher medical costs.

A straightforward strategy to address this issue is to perform susceptibility testing for clarithromycin. It is now well established that clarithromycin resistance can be detected by identifying specific point mutations through molecular methods.⁴,⁵,⁶ Resistance is primarily associated with mutations in 23S rRNA genes, with A2143G, A2142G, and A2142C accounting for the majority of clinically relevant mutations.⁷

A recent study by our group (Phase I) compared the eradication rates of tailored therapy based on genotypic resistance with those of empirical therapy for first-line H. pylori treatment as a Phase I study.⁸ We found that tailored therapy yielded superior eradication rates. However, our study included both 7-day and 14-day regimens, so the optimal duration of tailored therapy could not be conclusively determined. Therefore, we planned a Phase II study comparing 14-day empirical therapy with 7-day tailored therapy.

According to current Korean guidelines, 14-day clarithromycin-based triple therapy (TT) is recommended when prescribed empirically.⁹ In contrast, a 7-day regimen is advised when clarithromycin susceptibility testing is conducted. Nonetheless, few studies have directly compared 14-day empirical therapy with 7-day tailored therapy. Ideally, a shorter treatment regimen can reduce antibiotic exposure, which may in turn decrease the risk of adverse events and lower healthcare costs.

The primary aim of this study was to compare the efficacy of PCR-based tailored therapy with empirical therapy for H. pylori eradication. Specifically, we sought to determine whether the eradication rate of the 7-day tailored therapy was non-inferior to that of the 14-day empirical therapy. The secondary aim was to assess patient compliance and the incidence of adverse events associated with each treatment regimen.

MATERIALS AND METHODS

Study design and patients

This was a nationwide, multicenter, randomized controlled trial. The study was conducted in 10 institutions across five regions of Korea, including Seoul, Incheon and Gyeonggi, Gwangju and Jeolla, Daegu and Gyeongbuk, and Busan and Gyeongnam. Participants were randomly assigned to receive either a 14-day empirical treatment or a 7-day tailored therapy based on genotypic resistance. This study was approved by the Institutional Review Boards of each participating institution and by the Ministry of Food and Drug Safety of the Republic of Korea (20210057763). The trial was registered with ClinicalTrials.gov (NCT04147065) and the Clinical Research Information Services (CRIS) (KCT0004945). All procedures were conducted in accordance with the Declaration of Helsinki for research involving human subjects.

Individuals aged 19 to 79 years who provided informed consent were eligible for enrollment. H. pylori infection was initially confirmed using the urea breath test (UBT). Those who tested positive underwent esophagogastroduodenoscopy (EGD) for further evaluation. In the tailored group, gastric mucosal biopsies were obtained during EGD for Dual Priming Oligonucleotide-Based Multiplex Polymerase Chain Reaction (DPO-PCR) to assess genotypic resistance.

Exclusion criteria were as follows: 1) use of antibiotics within 1 month prior to enrollment; 2) use of acid suppressants such as H₂ antagonist, proton pump inhibitor (PPI), or potassium competitive acid blocker (P-CAB) within 2 weeks prior to enrollment; 3) previous H. pylori eradication therapy; 4) diagnosis of active peptic ulcers, marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type, or early gastric cancer requiring H. pylori treatment, including patients who had undergone endoscopic resection for early gastric cancer; 5) history of upper gastrointestinal surgery; 6) high risk of gastrointestinal bleeding; 7) presence of other gastrointestinal diseases requiring immediate treatment; 8) known hypersensitivity or adverse reactions to study medications; 9) pregnant or breastfeeding women; 10) history of alcohol or substance abuse; and 11) any other condition deemed inappropriate for study participation by the principal investigator at each site.

Endoscopic procedures and DPO-PCR study

EGD was performed using standard procedures. In the tailored therapy group, one biopsy specimen each from antrum and corpus of the stomach was obtained for the DPO-PCR assay (Seeplex ClaR-H. pylori ACE Detection; Seegene Institute of Life Science, Seoul, Korea). Additionally, one biopsy specimen each from antrum and corpus was placed in an Eppendorf tube and preserved either on dry ice or at -80℃ for subsequent culture and antibiotic susceptibility testing. Antibiotic susceptibility testing was conducted at a designated central laboratory.

The detection of H. pylori and the identification of A2142G and A2143G mutations via the DPO-PCR assay have been validated in previous studies.⁴,⁵,⁶ Similarly, methods for H. pylori culture and antibiotic susceptibility testing have also been well-documented in prior research.

Randomization and intervention

To minimize bias and ensure comparability, this study employed a random allocation process in which participants were assigned identification numbers rather than names. All allocations utilized block randomization to enhance unpredictability and reduce bias. An independent statistician generated random numbers using SAS version 9.4 (SAS Institute, Cary, NC, USA). Treatment allocations were concealed in opaque, sealed envelopes, which were opened only at the time of assignment. Once opened, the corresponding treatment group was prescribed and recorded. The allocation code was fixed and could not be reassigned, even if participants later withdrew consent.

Participants who tested positive for H. pylori via a UBT were randomly assigned in a 1:1 ratio to either the empirical therapy group or tailored therapy group. In the tailored therapy group, allocation was further guided by the DPO-PCR results. Participants with wild-type strains were assigned to a 7-day TT regimen, while those with mutations received a 7-day bismuth quadruple therapy (BQT) regimen.

TT included pantoprazole 40 mg, amoxicillin 1 g, and clarithromycin 500 mg, each administered twice daily. BQT consisted of pantoprazole 40 mg twice daily, metronidazole 500 mg three times daily, and bismuth 300 mg and tetracycline 500 mg four times daily.

Participants who failed eradication after TT received BQT regimens for 7 or 14 days. Those who failed eradication after BQT received levofloxacin-based TT (L-TT). L-TT consisted of pantoprazole 40 mg twice daily, amoxicillin 1 g twice daily, and levofloxacin 500 mg once daily for 10 days.

Outcome assessment

Eradication status was assessed using ¹³C-UBT at least 4 weeks after the completion of therapy. Prior to undergoing the ¹³C-UBT, participants were instructed to discontinue the use of H₂ antagonist, PPI, or P-CAB for a minimum duration of 2 weeks. Participants were also asked to report any adverse events throughout the study period. A standardized interview was conducted post-treatment to evaluate adverse effects and medication adherence. Poor compliance was defined as taking less than 80% of the prescribed medication.

Eradication rates were evaluated using both intention-to-treat (ITT) and per-protocol (PP) analyses. The ITT analysis included all randomized participants, while the PP analysis excluded those lost to follow-up and those with medication adherence below 80%.

Sample size calculation

The primary objective of this study was to assess whether the eradication success rate of a 7-day tailored therapy was non-inferior to that of a 14-day empirical therapy. The eradication rate of the 14-day empirical therapy was assumed to be 76.4%.⁹ Based on this assumption, a sample size of 284 participants per group was calculated to demonstrate the non-inferiority of the tailored therapy, with a non-inferiority margin of 10%. To account for an anticipated dropout rate of 10%, the final target enrollment was set at 315 participants per group.

Statistical analysis

Demographic and clinicopathological data were analyzed using Pearson’s χ² test, Fisher’s exact test, and Student’s t-test, as appropriate. Categorical variables were assessed using Pearson χ² test or Fisher’s exact test, while continuous variables were analyzed using the Student’s t-test. A p value less than 0.05 was considered statistically significant. All statistical analyses were conducted using the Statistical Package for the Social Sciences version 19.0 (IBM, Corp., Armonk, NY, USA).

RESULTS

Study population and baseline characteristics

The study was terminated prior to enrolling the initially planned number of participants due to the end of the research funding period. A total of 102 participants who underwent randomization between September 2023 and May 2025 were included in this study (Fig. 1), with 55 assigned to the empirical therapy group and 47 to the tailored therapy group. In the empirical group, two participants were lost to follow-up. In the tailored group, one participant was lost to follow-up and one withdrew from the study due to adverse events. Consequently, 98 participants were included in the PP population. The baseline demographic characteristics of the two groups were comparable (Table 1). The clarithromycin resistance rate, as determined by the DPO-PCR test, was 36.2% (17/47).

Fig. 1. Flowdiagram of patients enrolled in the study. f/u, follow-up; AE, adverse event.

Table 1. Baseline Characteristics of the Enrolled Patients.

	Empirical (n=55)	Tailored (n=47)	p
Age (yr)	59.0±11.1	58.7±11.7	0.882
Male	27 (49.0)	24 (51.1)	>0.999
Smoking	6 (11.0)	4 (8.5)	0.749*
Alcohol	22 (40.0)	17 (36.2)	0.847
Family history of gastric cancer	8 (14.5)	7 (14.9)	>0.999*
Diabetes	7 (12.7)	4 (8.5)	0.541*
Hypertension	13 (23.6)	12 (25.5)	>0.999

Numbers are presented as mean±SD or n (%).

^*Fisher’s exact test.

Eradication rates of empirical and tailored therapy

In the ITT analysis, the eradication rates were 65.5% (36/55) in the empirical therapy group and 82.9% (39/47) in the tailored therapy group (Table 2). In the PP analysis, the eradication rates were 67.9% (36/53) and 86.7% (39/45), respectively. No statistically significant difference was observed between the two groups in either ITT or PP analysis.

Table 2. Eradication Rates of Empirical and Tailored Therapy.

	Empirical (n=55)	Tailored (n=47)	p
ITT	65.5 (36/55)	82.9 (39/47)	0.076
PP	67.9 (36/53)	86.7 (39/45)	0.052

ITT, intention-to-treat; PP, per-protocol.

Numbers are presented as % (n).

Among participants without point mutations, the ITT eradication rate with the 7-day TT regimen was 83.3% [95% confidence interval (CI), 65.3–94.4; 25/30], and the corresponding PP eradication rate was 86.2% (95% CI, 68.3–96.1; 25/29). In participants with point mutations, the ITT eradication rate with the 7-day BQT regimen was 86.2% (95% CI, 68.3–96.1; 14/17), with a PP eradication rate of 87.5% (95% CI, 61.7–98.5; 14/16).

Adverse events and compliance

Adverse events were reported in 14 participants (25.5%) in the empirical therapy group and 15 participants (31.9%) in the tailored therapy group (Table 3), with no significant difference in incidence between the two groups. Dysgeusia was the most commonly reported adverse event in both groups. Treatment compliance was comparable across groups; however, one participant in the tailored therapy group withdrew from the study due to adverse events. Most adverse events were mild in severity, classified as below Grade II.

Table 3. Adverse Events and Compliance.

	Empirical	Tailored	p
Any adverse events	14	15	0.617
Dysgeusia	11	11
Epigastric discomfort	2	0
Diarrhea	1	0
Nausea	0	2
Itching	0	1
General weakness	0	1
Compliance	53/53	45/46	0.465*

^*Fisher’s exact test.

DISCUSSION

Current Korean guidelines recommend 14-day TT therapy when prescribed empirically, and either 7-day TT or BQT when guided by antibiotic susceptibility testing.⁹ To our knowledge, no randomized studies have directly compared the eradication rates of 14-day empirical therapy with those of 7-day tailored therapy in Korea. In our study, the eradication rate of 7-day tailored therapy based on genotypic resistance was approximately 20% higher than that of 14-day empirical therapy. Although the difference was not statistically significant, this may be attributed to the limited sample size, as the study was prematurely terminated due to sponsor-related constraints. Based on our data, a minimum of 75 participants per group would be required to demonstrate statistical significance. However, this study plays a preliminary role in guiding future research.

Antimicrobial therapy for H. pylori has traditionally been prescribed empirically rather than based on antimicrobial susceptibility testing.¹⁰ Until recently, treatment recommendations have largely overlooked the principles of antibiotic stewardship.¹¹ Clarithromycin-based TT regimens remain widely used, despite rising clarithromycin resistance and declining eradication rates. This is reflected in the current Korean guidelines, which continue to recommend a 14-day course of empirical TT. However, in our study, empirical TT yielded disappointing outcomes, raising concerns about its continued use and prompting reconsideration of TT-based prescriptions. Given the increasing prevalence of clarithromycin-resistant H. pylori, the Maastricht VI consensus recommends performing susceptibility testing prior to prescribing clarithromycin-containing regimens.¹ Similarly, recent American guidelines advise against the use of clarithromycin- or levofloxacin-based therapies in the absence of confirmed susceptibility.¹ Notably, a recent study reported a PP eradication rate of 89.4% for 7-day tailored therapy, even with a clarithromycin resistance rate of 34.5%.¹² Another randomized trial comparing 7-day and 14-day tailored therapies found comparable eradication rates of 87.9% and 89.1%, respectively.¹³ Finally, a retrospective study reported that 7-day TT was as effective as 14-day TT in patients without point mutations identified by PCR tests.¹⁴ These findings suggest that a 7-day tailored regimen may be sufficient when guided by susceptibility testing.

Although several studies have compared the eradication rates of tailored therapy versus empirical therapy, most have evaluated regimens with the same treatment duration.¹⁵,¹⁶,¹⁷,¹⁸ Few studies have investigated whether tailored therapy can reduce the duration of treatment while maintaining efficacy compared to empirical therapy. In our previous study, we reported that the eradication rate of tailored therapy was superior to that of empirical therapy.⁸ However, both 7-day and 14-day regimens were included in the tailored and empirical groups, making it unclear whether a shorter duration of tailored therapy would be superior to a longer duration of empirical therapy.

Our study demonstrated the non-inferiority of the 7-day tailored therapy regimen relative to the 14-day empirical regimen. These findings highlight an additional advantage of tailored therapy: achieving superior or comparable eradication rates with a shorter treatment duration. This supports the concept that prescriptions guided by antimicrobial susceptibility not only improve clinical outcomes but also reduce adverse drug events, selective antibiotic pressure, and the economic burden associated with inappropriate antibiotic use.¹⁹ The authors are currently conducting a study to evaluate whether tailored therapy is more cost-effective than empirical therapy.

However, our study had several limitations. Due to sponsorrelated recommendations, the trial was terminated prematurely, and we were unable to recruit the originally planned number of participants. Although tailored therapy showed superior eradication rates compared to empirical therapy, the study may have been underpowered to detect statistically significant differences. Second, the PP eradication rate of empirical therapy in our study was 67.9%, which was lower than that reported in previous studies.⁹ This may have been due to the relatively small number of enrolled patients or the high prevalence of clarithromycin resistance in our study population. Peptic ulcer disease, endoscopic resection for early gastric cancer, and MALT lymphoma were not included in our study. Including these indications in our clinical study was deemed inappropriate by the Korean Ministry of Food and Drug Safety, as they are absolute indications for eradication and are reimbursed by the Korean government.

In conclusion, our study demonstrated a tendency for 7-day tailored therapy based on genotypic resistance to be superior to 14-day empirical therapy for the eradication of H. pylori. No significant differences were observed between the two groups in terms of adverse events or treatment compliance. These findings further support the clinical utility of antibiotic susceptibility-guided therapy in improving eradication outcomes.