Regional multi-center randomized trial of three vonoprazan-amoxicillin dosing regimens for Helicobacter pylori eradication in Sichuan Province, China

Abstract

BACKGROUND

Helicobacter pylori (H. pylori) infection is highly prevalent worldwide, and rising antibiotic resistance has reduced the efficacy of standard therapy, underscoring the need for simplified and better-tolerated regimens.

AIM

To evaluate the efficacy, safety, and optimal dosing of vonoprazan (VPZ)-amoxicillin (AMO) dual therapy in a non-inferiority randomized trial for H. pylori eradication.

METHODS

In this multi-center, randomized trial conducted at 17 hospitals in Sichuan Province, China, 1717 adults with confirmed infection were assigned (1:1:1) to 14-day regimens: (1) VPZ 20 mg BID + AMO 0.5 g QID; (2) 0.75 g QID; or (3) 1.0 g TID. The primary endpoint was the eradication rate based on intention-to-treat (ITT) and per-protocol (PP) analyses; secondary endpoints included adverse events (AEs) and treatment compliance.

RESULTS

Eradication rates were consistently high (92.35%-97.43%). In the 0.5 g QID group, ITT and PP eradication rates were 93.3% (95%CI: 91.2-95.1) and 97.4% (95%CI: 95.7-98.5), respectively, with no significant differences among groups (P > 0.05). Compliance ranged from 98.1% to 98.3%, and AEs were infrequent (5.2%-7.5%), predominantly mild gastrointestinal symptoms, which occurred least often in the 0.5 g QID group.

CONCLUSION

VPZ-AMO dual therapy achieved excellent eradication, safety, and patient compliance. All regimens were similarly effective, whereas the 0.5 g QID dosing strategy offered the most favorable balance of efficacy and tolerability, supporting its use as a first-line option in high-prevalence settings.

Key Words: Vonoprazan; Amoxicillin; Helicobacter pylori; Potassium-competitive acid blockers; Dose

Core Tip: This multi-center randomized non-inferiority trial compared three vonoprazan (VPZ) plus amoxicillin (AMO) dual-therapy regimens: AMO 0.5 g QID, 0.75 g QID, and 1.0 g TID. All regimens achieved high eradication with excellent compliance and low adverse-event rates. The low-dose, high-frequency option (0.5 g QID) provided efficacy comparable to higher doses with superior tolerability, supporting dose optimization of VPZ-AMO as a practical first-line strategy in high-prevalence regions.

INTRODUCTION

Helicobacter pylori (H. pylori) is a pathogenic microorganism that colonizes the gastric mucosa for prolonged durations. About half of the global population is infected[1]. H. pylori is closely linked to chronic gastritis, peptic ulcer disease, and multiple gastric disorders[2-5]. Eradication substantially decreases the risk of these conditions and improves clinical outcomes[6,7]. International and national expert consensuses, including the Maastricht VI/Florence Consensus and the most recent Chinese guidelines, recommend active eradication in infected patients without contraindications[8,9]. Resistance to clarithromycin and metronidazole used in conventional triple or quadruple therapy has continued to rise[10]. Although international recommendations advise clarithromycin susceptibility testing before use, timely access to such testing remains limited in many regions of China, reducing the practical effectiveness of standard regimens. By contrast, the resistance rate of amoxicillin (AMO) in China has remained very low (generally < 3%) for many years[11]. AMO is typically combined with potent acid suppression, as its antibacterial activity declines markedly in low-pH environments. Moreover, monotherapy with AMO does not promote resistance development in H. pylori, and maintaining intragastric pH above 6 has been shown to correlate strongly with successful eradication.

Vonoprazan (VPZ), a potassium-competitive acid blocker, offers advantages over traditional proton pump inhibitors (PPIs), including acid stability without activation, rapid onset, prolonged suppression of gastric acid, and low interindividual variability[12]. It also demonstrates superior nocturnal acid suppression compared with esomeprazole and is not influenced by CYP2C19 polymorphisms[13]. AMO is advantageous due to its low resistance rate, availability, and cost-effectiveness in China[14].

Eradication with conventional triple therapy has declined substantially as resistance has increased. The Fifth National Consensus Report on the Management of H. pylori Infection in China (2017) documented resistance rates exceeding the international 15% alert threshold for clarithromycin (28.9%), metronidazole (63.8%), and levofloxacin (28.8%)[15]. Consequently, standard PPI-based triple therapy is no longer recommended in high dual-resistance regions unless susceptibility data are available. In such settings, guidelines endorse bismuth-based or non-bismuth quadruple regimens that combine PPIs with multiple antibiotics to maintain acceptable eradication rates[16,17]. However, these approaches are costly, have higher rates of adverse effects, and reduce adherence. Repeated therapeutic failures can further promote multi-drug resistance. VPZ-AMO dual therapy has recently gained attention as a simplified alternative with comparable efficacy and improved tolerability. A domestic randomized controlled trial using 1.0 g AMO BID for 10 days showed suboptimal eradication, whereas 14-day VPZ-AMO regimens achieved superior outcomes, potentially reflecting regional susceptibility differences[18]. Prolonging dual therapy to 14 days consistently yields > 90% eradication in diverse populations, with both standard-dose (1.0 g BID) and high-dose (1.0 g TID) AMO regimens showing similar success in multi-center Chinese studies[19].

However, evidence for lower-dose strategies (e.g., 0.5 g QID) is still limited. Such dosing may offer a better balance of efficacy, adherence, and tolerability. To address this gap, the present multi-center randomized trial was designed to evaluate the eradication efficacy and safety of three VPZ-AMO dosing regimens, including the previously underexplored 0.5 g QID strategy.

MATERIALS AND METHODS

Study participants

This study enrolled 1717 treatment-naive patients with H. pylori infection from 34 tertiary hospitals (Class III Grade A or B) in Sichuan Province between November 2022 and March 2023 using a random number table method. Participants were assigned into three groups: (1) Standard-dose conventional treatment group (568 cases); (2) High-dose, high-frequency treatment group (574 cases); and (3) High-dose, low-frequency treatment group (575 cases).

Sample size and non-inferiority margin

The trial was powered to demonstrate non-inferiority of each test arm vs the reference (0.5 g QID) on the risk-difference scale with a prespecified margin of -10%, consistent with prior H. pylori eradication trials. Assuming a common eradication rate of 90%, a one-sided α of 0.0125 (Bonferroni-adjusted for two comparisons) and 80% power, the required sample size was approximately 171 participants per arm using the Farrington-Manning approximation \big(n\approx [(z_{1-\alpha}+z_{1-\beta})2\cdot 2p(1-p)]/\Delta2\big). Allowing for 10% non-evaluable cases, approximately 190 per arm were required. The final randomization (568/574/575) exceeded the minimum requirement, ensuring sufficient statistical power for primary and subgroup analyses.

Treatment protocols

The three groups received: (1) Standard-dose conventional group (0.5 g-QID): VPZ 20 mg twice daily (before breakfast and dinner) plus AMO 500 mg four times daily (after breakfast, lunch, dinner, and at bedtime) for 14 days; (2) High-dose, high-frequency group (0.75 g-QID): VPZ 20 mg twice daily plus AMO 750 mg four times daily for 14 days; and (3) High-dose, low-frequency group (1.0 g-TID): VPZ 20 mg twice daily plus AMO 1.0 g three times daily for 14 days.

AMO (brand name: Nomoling) was manufactured by Shijiazhuang Ouyi Pharmaceutical Co., Ltd. (National Drug Approval Number H13023964) and supplied as 0.25 g tablets.

VPZ fumarate (brand name: Wakol) was produced by Takeda Pharmaceutical Co., Ltd. (Tianjin) (National Drug Approval Number J20200011) and supplied as 20 mg tablets.

Baseline characteristics

The sex and age distribution of the three groups was as follows: (1) Standard-dose conventional group: 230 men and 338 women, mean age 46 years; (2) High-dose, high-frequency group: 207 men and 367 women, mean age 47 years; and (3) High-dose, low-frequency group: 257 men and 318 women, mean age 45 years.

Inclusion criteria

(1) Adults aged 18-70 years; (2) No use of PPIs, H₂ receptor antagonists, or other medications affecting H. pylori activity within 2 weeks before treatment, and no antibiotics, bismuth, or Chinese herbal medicines within 4 weeks before treatment; (3) Initial diagnosis of H. pylori positivity by ¹³C/¹⁴C-urea breath test (UBT), rapid urease test, or histopathology, with no prior eradication therapy; (4) Esophagogastroduodenoscopy performed within the past year; and (5) Written informed consent with complete medical documentation and follow-up information available.

Exclusion criteria

(1) Systemic lupus erythematosus, acquired immunodeficiency syndrome, or human immunodeficiency virus infection; hepatitis B surface antigen positivity or hepatitis C virus antibody/RNA positivity; serum creatinine > 2 mg/dL (177 μmol/L); alanine aminotransferase or aspartate aminotransferase > 2 × upper limit of normal, or total bilirubin > 2 × upper limit of normal; or clinically significant disease involving the central nervous system, cardiovascular, respiratory, hepatic, renal, metabolic, gastrointestinal, urinary, endocrine, or hematologic systems; (2) Known allergy to penicillin, AMO, or VPZ; (3) Organic gastrointestinal lesions (tumor, active bleeding, etc.); (4) Psychiatric disorders or communication barriers; (5) Pregnancy or lactation; and (6) Participation in another clinical trial.

Treatment was discontinued if: (1) Intolerable adverse reactions occurred; (2) An intercurrent illness interfered with the trial; (3) The patient was lost to follow-up; or (4) Voluntary withdrawal occurred.

The technical roadmap of this study is shown in Figure 1. This study was approved by the Ethics Committee and the Clinical Pharmacy Committee (approval number KY2022272). The therapeutic agents and dosages were consistent with clinical guidelines. The trial was registered at the Chinese Clinical Trial Registry (ChiCTR2200065282), conducted in accordance with the Declaration of Helsinki, and reported according to CONSORT guidelines.

Figure 1 Flowchart of the participant enrollment, follow-up, and study completion based on the CONSORT guidelines. ITT: Intention-to-treat; PP: Per-protocol.

Randomization and interventions

Participants were competitively enrolled across study centers according to a pre-generated randomization list created using R software (version 4.3.2) by an independent statistician uninvolved in patient recruitment or treatment. Eligible patients were sequentially assigned to one of three treatment regimens in a 1:1:1 ratio based on the randomization sequence. Each center obtained the next available allocation number to ensure balanced enrollment across sites while maintaining strict allocation concealment throughout the process.

Follow-up

All treatments were prescribed by trained outpatient physicians at each participating center, who also provided verbal counseling and written instructions. To ensure protocol fidelity, all sites used a standardized drug administration plan and identical medications. Concomitant treatment of unrelated comorbidities (e.g., antihypertensive or antidiabetic drugs) was permitted and documented when applicable. Follow-up assessments were performed mid-treatment and upon therapy completion. Medication adherence was evaluated by pill counts during scheduled telephone follow-up. Adverse events (AEs) were actively monitored throughout treatment, and therapy was discontinued if clinically indicated. No prespecified interim analysis or formal stopping rules were applied.

All participants were required to undergo regular follow-up during the treatment period. Investigators contacted patients via WeChat, telephone, and other communication tools (including audio recordings) to document adherence and AEs. Smoking and alcohol consumption were strictly prohibited throughout treatment and for at least one week after discontinuation. Patients returned to the hospital ≥ 4 weeks after treatment completion to determine whether H. pylori had been eradicated.

Outcomes

Eradication of H. pylori was evaluated uniformly across treatment groups. Follow-up testing was conducted 4-6 weeks after therapy to avoid false-negative results from recent proton-pump inhibitor or antibiotic exposure. The ¹³C-urea breath test (¹³C-UBT) was used as the standard diagnostic method based on national and international consensus recommendations. A negative ¹³C-UBT result was defined as successful eradication. Stool antigen or biopsy-based methods were used for patients who could not undergo UBT. Follow-up procedures were performed by blinded assessors independent of treatment allocation. To minimize intercenter variability, all study sites used the same UBT analyzer and reagents under centralized quality control, and technicians received standardized training before study initiation.

Secondary outcomes included symptom relief, treatment compliance, and the incidence and severity of AEs. Symptom improvement was assessed using a structured treatment evaluation form (Table 1). The symptoms assessed included upper abdominal pain, postprandial discomfort, and loss of appetite. Symptom severity was graded as follows: 0 points (no symptoms); 1 point (mild symptoms); 2 points (moderate and tolerable); 3 points (severe, affecting work or daily life); and 4 points (very severe, significantly impairing normal life activities). The total score was the sum of individual symptom scores. Treatment efficacy was categorized as: (1) Markedly effective, defined as a post-treatment score ≤ one-third of the pretreatment score; (2) Effective, defined as a reduction > one-third but ≤ two-thirds; and (3) Ineffective, defined as a reduction ≤ one-third or deterioration. “Markedly effective” and “effective” were considered clinically effective overall. Poor adherence was defined as < 80% medication intake or ≥ 20% missed doses.

Table 1 Therapeutic effects.

Efficacy observation table
Symptom	Score before treatment	Score after treatment
Nausea
Vomiting
Loss of appetite
Abdominal distension
Abdominal pain
Diarrhea
Constipation
Belching
Acid regurgitation
Bitter taste
Heartburn
Halitosis
Total score

Symptom assessment and efficacy evaluation: Symptoms were scored from 0 (asymptomatic) to 4 (most severe). Efficacy was categorized based on the reduction in total symptom score post-treatment: Markedly effective (≤ 1/3 of baseline), effective (≤ 2/3 of baseline), or ineffective (> 2/3 of baseline). The overall clinical effectiveness rate included both "Markedly Effective" and "Effective" outcomes.

AEs were prospectively documented throughout treatment using a standardized checklist covering gastrointestinal (nausea, vomiting, abdominal pain, diarrhea, bloating, constipation, black stool) and systemic symptoms (headache, dizziness, rash, palpitations). Investigators blinded to allocation classified each AE as mild (transient and tolerable), moderate (causing functional limitation), or severe (interfering with normal activities).

Statistical analysis

All statistical analyses were performed using R software (version 4.3.2). H. pylori eradication was assessed using intention-to-treat (ITT), modified ITT (mITT), and per-protocol (PP) analyses. The mITT population included all participants who received at least one dose of therapy, while the PP population included those who completed treatment and underwent a ¹³C-UBT ≥ 4 weeks after therapy. Participants were excluded from the PP analysis if they discontinued treatment, were lost to follow-up, or failed to complete post-treatment testing.

Continuous variables were first tested for normality using the Shapiro-Wilk test. Normally distributed variables are expressed as mean ± SD and compared using one-way ANOVA or independent-samples t-tests, as appropriate. Non-normally distributed variables are reported as median (IQR) and compared using the Kruskal-Wallis H test or Wilcoxon rank-sum test. Categorical variables are expressed as frequencies and percentages and compared using the χ² test or Fisher’s exact test when expected cell counts were < 5. The primary outcome was analyzed within a non-inferiority framework, and non-inferiority was confirmed when the lower bound of the two-sided 95%CI for the eradication-rate difference exceeded -10%, the prespecified non-inferiority margin.

RESULTS

Baseline characteristics of the participants

A total of 1717 patients were enrolled, with 568574, and 575 patients assigned to the 0.5 g QID, 0.75 g QID, and 1.0 g TID groups, respectively. Most baseline characteristics were generally comparable across the three groups (Table 2). The mean age of the 0.75 g QID group [47 (36-57) years] was slightly higher than that of the 0.5 g QID [46 (35-54) years] and 1.0 g TID groups [45 (33-55) years], and the difference was statistically significant (P = 0.021, Kruskal-Wallis test). The proportion of female participants also differed significantly between groups (χ²= 8.830, P = 0.012), with the highest percentage observed in the 0.75 g QID group (63.9%) and the lowest in the 1.0 g TID group (55.3%). Rates of loss to follow-up (2.5%, 1.7%, and 3.0%) and poor adherence (1.8%, 1.9%, and 1.7%) did not differ significantly among the treatment arms (χ²= 1.411, P = 0.494; χ²= 0.037, P = 0.982). Symptom relief outcomes were also similar (χ²= 6.180, P = 0.186). The percentages of markedly effective cases increased progressively across the three groups (83.8%, 88.7%, and 91.9%), and the difference was statistically significant (χ²= 8.140, P = 0.017). The median pretreatment symptom scores were 2.0 (IQR 2.0-4.0), 3.0 (IQR 2.0-4.0), and 3.0 (IQR 2.0-4.0) and decreased after therapy to 0.0 (IQR 0.0-0.0), 0.0 (IQR 0.0-0.0), and 0.0 (IQR 0.0-0.0), with no statistically significant between-group differences (P = 0.170 and P = 0.169 for pretreatment and posttreatment scores, respectively; Kruskal-Wallis test).

Table 2 Baseline demographics and clinical symptoms, n (%).

		0.5 g-QID	0.75 g-QID	1.0 g-TID	P value
		568	574	575
Gender	Female	338 (59.5)	367 (63.9)	318 (55.3)	0.012
	Male	230 (40.5)	207 (36.1)	257 (44.7)
Age [median (IQR)]		46.0 (35.0-54.0)	47.0 (36.0-57.0)	45.0 (33.0-55.0)	0.021
	Lost to follow-up	14 (2.5)	10 (1.7)	17 (3.0)	0.494
	Poor adherence	10 (1.8)	11 (1.9)	10 (1.7)	0.982
Symptom relief group	Asymptomatic	340 (59.9)	317 (55.2)	325 (56.5)	0.186
	No symptom relief	6 (1.1)	7 (1.2)	9 (1.6)
	Symptom relief	208 (36.6)	240 (41.8)	224 (39.0)
Efficacy	Markedly effective	171 (83.8)	204 (88.7)	203 (91.9)	0.017
	Ineffective	21 (10.3)	10 (4.3)	7 (3.2)
	Effective	12 (5.9)	16 (7.0)	11 (5.0)
Pretreatment score [median (IQR)]		2.0 (2.0-4.0)	3.0 (2.0-4.0)	3.0 (2.0-4.0)	0.170
Post treatment score [median (IQR)]		0.0 (0.0-0.0)	0.0 (0.0-0.0)	0.0 (0.0-0.0)	0.169
Adverse events		31 (5.46)	30 (5.23)	43 (7.48)	0.187

P < 0.05 was considered statistically significant. Between-group differences were assessed using χ² tests for categorical variables and Kruskal-Wallis test for continuous variables (age, pretreatment score, and posttreatment score).

H. pylori eradication rate

As shown in Table 3, eradication rates were consistently high in all three dosing groups. In the ITT analysis, eradication rates were 93.31% (95%CI: 91.15-95.09) for the 0.5 g QID group, 93.55% (95%CI: 91.42-95.23) for the 0.75 g QID group, and 92.35% (95%CI: 90.11-94.17) for the 1.0 g TID group (P = 0.696). In the mITT analysis, the rates were 95.67% (95%CI: 93.84-96.98), 95.21% (95%CI: 93.33-96.55), and 95.16% (95%CI: 93.27-96.51), respectively (P = 0.911). In the PP analysis, eradication rates remained high at 97.43%, 97.11%, and 96.90% across the three groups, with no statistically significant differences (P = 0.870). Collectively, all regimens achieved eradication rates exceeding 92% in the ITT analysis and 96% in the PP analysis. The low-dose, high-frequency regimen (0.5 g QID) was non-inferior to the higher-dose regimens, providing comparable clinical benefit while potentially minimizing pill burden. These results support 0.5 g QID as a clinically efficient and practical option for H. pylori eradication, especially in high-prevalence regions.

Table 3 Eradication rate of Helicobacter pylori.

Dosage	0.5 g-QID (95%CI) (%)	0.75 g-QID (95%CI) (%)	1 g-TID (95%CI) (%)	P value
ITT	93.31	93.55	92.35	0.696
95%CI	91.15-95.09	91.42-95.23	90.11-94.17
mITT	95.67	95.21	95.16	0.911
95%CI	93.84-96.98	93.33-96.55	93.27-96.51
PP	97.43	97.11	96.90	0.870
95%CI	95.73-98.46	95.35-98.21	95.09-98.05

ITT: Intention-to-treat; PP: Per-protocol; mITT: Modified intention-to-treat.

Efficacy assessment

No statistically significant difference was observed in the overall distribution of symptom relief among the three groups (P = 0.480). The rates of loss to follow-up were 2.5%, 1.7%, and 3.0% in the 0.5 g QID, 0.75 g QID, and 1.0 g TID groups, respectively. The proportions of asymptomatic patients were 59.9%, 55.2%, and 56.5%, while unrelieved symptoms accounted for 1.1%, 1.2%, and 1.6%. The proportions of patients reporting symptom improvement were 36.6%, 41.8%, and 39.0%, respectively. Markedly effective cases accounted for 83.8%, 88.7%, and 91.9% (P = 0.017), and the combined markedly effective plus effective rates were 89.7%, 95.7%, and 96.8%, indicating symptom improvement across all regimens.

Adherence and AEs

As shown in Table 4, all three regimens were well tolerated, with no serious AEs reported. The 0.5 g QID group demonstrated the lowest incidence of adverse reactions, with mild events such as nausea (1.8%), bloating (1.6%), diarrhea (1.4%), and abdominal discomfort (0.9%) occurring at low frequencies. No cases of loss of appetite, dry mouth, altered taste, or heartburn were reported in this group. In contrast, the 0.75 g QID and 1.0 g TID groups exhibited overall low adverse-event rates but experienced a slightly broader range of side effects, including reduced appetite, dry mouth, and taste disturbances, which were not observed in the 0.5 g QID group. Most AEs were mild gastrointestinal symptoms that resolved spontaneously or with minimal supportive care. The overall incidence of AEs was low and comparable among the three dosing schedules (5.5%, 5.2%, and 7.5%; P = 0.187).

Table 4 Adverse events, n (%).

ADR	0.5 g-QID	0.75 g-QID	1.0 g-TID	P value
Nausea	10 (1.8)	9 (1.6)	10 (1.7)	0.8215
Vomiting	2 (0.4)	2 (0.3)	0 (0.0)	0.2467
Decreased appetite	0 (0.0)	1 (0.2)	0 (0.0)	0.4996
Abdominal distension	9 (1.6)	10 (1.7)	7 (1.2)	0.4772
Abdominal pain	5 (0.9)	4 (0.7)	7 (1.2)	0.5469
Diarrhea	8 (1.4)	11 (1.9)	8 (1.4)	0.4996
Constipation	1 (0.2)	3 (0.5)	3 (0.5)	0.6244
Black stool	0 (0.0)	1 (0.2)	0 (0.0)	0.4996
Altered taste	0 (0.0)	1 (0.2)	0 (0.0)	0.4996
Xerostomia	0 (0.0)	2 (0.3)	5 (0.9)	0.0620
Bitter taste in mouth	0 (0.0)	1 (0.2)	0 (0.0)	0.4996
Headache	1 (0.2)	0 (0.0)	0 (0.0)	0.4969
Dizziness	2 (0.4)	1 (0.2)	1 (0.2)	0.6224
Rash	1 (0.2)	0 (0.0)	3 (0.5)	0.2493
Chest tightness	1 (0.2)	0 (0.0)	0 (0.0)	0.4969
Palpitations	0 (0.0)	1 (0.2)	0 (0.0)	0.4996
Belching	1 (0.2)	1 (0.2)	0 (0.0)	0.4969
Heartburn	0 (0.0)	0 (0.0)	1 (0.2)	1.0000

ADR: Adverse drug reactions.

Age-stratified analysis

In the age-stratified analysis (Table 5), eradication and adherence rates remained consistently high across all dosing regimens and age groups. For the 0.5 g QID regimen, eradication exceeded 94% among adults aged 18-59 years and remained > 84% in older participants (60-70 years), with adherence rates close to 99%. Although a mild age-related decline in the eradication rate was observed, the difference reached statistical significance (P < 0.05). A similar pattern was identified in the 0.75 g QID group, with eradication rates > 95% in younger and middle-aged participants and 81.7% in older adults (P < 0.05). In contrast, the 1 g TID regimen showed no statistically significant age-related variation in eradication efficacy (P > 0.05). AEs were infrequent across all age strata, occurring in ≤ 10% of participants, without clinically meaningful differences between subgroups.

Table 5 Age-stratified analysis of eradication efficacy, adherence, and adverse events across the three vonoprazan-amoxicillin regimens, n (%).

Regimen	Age group	n (ITT)	Eradicated	Adherence ≥ 80%	Adverse events	P value (by age)
0.5 g-QID	18-39	205	194 (94.6)	200 (97.6)	6 (2.9)	< 0.05
	40-59	285	270 (94.7)	281 (98.6)	21 (7.4)	< 0.05
	60-70	78	66 (84.6)	77 (98.7)	4 (5.1)	< 0.05
0.75 g-QID	18-39	188	179 (95.2)	181 (96.3)	19 (10.1)	< 0.05
	40-59	282	273 (96.8)	279 (98.9)	7 (2.5)	< 0.05
	60-70	104	85 (81.7)	103 (99.0)	4 (3.8)	< 0.05
1 g-TID	18-39	234	214 (91.5)	228 (97.4)	14 (6.0)	> 0.05
	40-59	281	265 (94.3)	277 (98.6)	28 (10.0)	> 0.05
	60-70	60	52 (86.7)	60 (100.0)	1 (1.7)	> 0.05

ITT: Intention-to-treat.

Overall, these findings indicate that both the 0.5 g QID and 0.75 g QID regimens achieved excellent eradication efficacy and adherence in younger and middle-aged adults. The 0.5 g QID regimen also maintained comparatively stable performance in older patients, further supporting its suitability as a practical and well-tolerated first-line option across age groups.

DISCUSSION

This large multi-center non-inferiority randomized controlled trial demonstrated that all three dosing regimens achieved eradication rates > 92% in the ITT analysis and > 96% in the PP analysis, surpassing the 90% benchmark recommended by the 2022 Chinese H. pylori guidelines and the Maastricht VI/Florence consensus report. Importantly[20], the low-dose, high-frequency regimen (0.5 g QID) was statistically non-inferior to higher-dose regimens while achieving excellent compliance (> 98%) and favorable safety outcomes, thereby filling the previous gap in evidence regarding whether prolonged low-dose regimens can maintain eradication efficacy. These results suggest that optimizing dose frequency, rather than simply increasing individual doses, can sustain high eradication rates while reducing treatment burden and adverse effects[11,21].

The findings are consistent with recent trials and real-world data from Japan, Korea, and other Asian countries[22], where VPZ-based dual therapy has shown robust eradication performance and potent acid suppression even in settings with rising antibiotic resistance[23]. Prior studies typically adopted fixed high-dose regimens (e.g., 0.75 g QID or 1.0 g TID), leaving uncertainty regarding comparative outcomes across different dosing strategies[24-26]. By systematically evaluating three clinically relevant regimens, this study provides the first large-scale evidence showing that more frequent administration of a lower individual dose can yield equivalent eradication, addressing a key gap highlighted in recent international consensus statements.

All three VPZ-AMO regimens demonstrated a favorable safety profile, with AEs occurring in < 8% of patients. Most AEs were mild gastrointestinal symptoms that resolved without the need for treatment interruption. The 0.5 g QID regimen had the lowest adverse-event incidence while delivering non-inferior eradication efficacy, indicating that dose escalation beyond 0.5 g does not further improve treatment effectiveness but may slightly increase gastrointestinal discomfort. These observations support the clinical adoption of the 0.5 g QID regimen as a practical, well-tolerated first-line strategy.

Compared with bismuth-containing quadruple therapy (BQT), the VPZ-AMO dual regimen represents a simpler and lower-burden alternative[27]. Although BQT can also achieve high eradication, it is commonly associated with gastrointestinal discomfort, complex dosing schedules, and a greater likelihood of drug interactions[28]. In this study, the per-patient cost of the VPZ-AMO regimen was 400 RMB (approximately 57.1 USD) compared with 746 RMB (approximately 106.6 USD) for BQT, representing a 46.4% cost reduction. This economic advantage, combined with good tolerability, supports the dual regimen as a strong first-line choice, especially for patients with drug intolerance, polypharmacy concerns, or for resource-limited clinical settings aiming to reduce treatment complexity[29].

According to the Maastricht VI/Florence consensus, effective H. pylori eradication requires potent and sustained gastric acid suppression to maintain intragastric pH between 6 and 7[19]. Existing trials have shown that the 14-day VA dual regimen is superior to BQT in several respects: VPZ is stable under acidic conditions, acts rapidly, and delivers strong acid suppression from day one; conventional PPIs have weaker pKa values (3.8-5.0), shorter half-lives (0.5-2.0 hours), and less consistent pH control; and the efficacy of PPIs is strongly influenced by CYP2C19 polymorphisms, whereas VPZ efficacy is unaffected by genotype differences, resulting in more consistent clinical outcomes[30-32].

AMO is a time-dependent antibiotic, and its bactericidal effect depends on maintaining plasma concentrations above the MIC (T > MIC). The 0.5 g QID regimen reduces fluctuations between peak and trough concentrations, thereby prolonging T > MIC and enabling continuous suppression of H. pylori growth while VPZ maintains gastric pH ≥ 6.0 for most of the day[33]. This favorable pharmacokinetic and pharmacodynamic profile enhances AMO stability and antibacterial potency in the gastric environment[34]. Together, these mechanistic features explain why more frequent administration of a lower dose can achieve comparable eradication efficacy while improving tolerability[35].

With global antimicrobial resistance increasing, treatment strategies that deliver optimal pharmacodynamic exposure while minimizing antibiotic overuse are essential[36]. By demonstrating that a low-dose, high-frequency regimen is non-inferior to higher-dose regimens, this trial supports rational antibiotic stewardship without compromising efficacy. Furthermore, the simplified dual regimen, which relies on two well-tolerated agents, is suitable for potential integration into large-scale screening and eradication programs, particularly in high-prevalence regions with constrained healthcare resources, where simplified protocols can improve scalability, adherence, and long-term sustainability.

The main strengths of this study include its large sample size (n = 1717), multi-center design, and rigorous randomization process, which collectively enhance the reliability and generalizability of the findings. The pragmatic design reflects real-world clinical practice and increases the external validity of the conclusions. In addition, the non-inferiority framework with a prespecified margin (-10%) is statistically robust and aligns with accepted standards in antimicrobial clinical trials.

However, some limitations should be acknowledged. First, all study sites were located within Sichuan Province, which may limit generalizability to populations with different genetic backgrounds, antimicrobial resistance patterns, or healthcare infrastructures. Second, the open-label design, although practical, may have introduced performance or detection bias despite the use of objective outcomes such as ¹³C-UBT confirmation. Third, this study did not examine post-eradication changes in gastric microbiota composition or evaluate long-term reinfection or recurrence.

The neutrophil-to-lymphocyte ratio (NLR) has recently been proposed as a simple, cost-effective marker of systemic inflammation and immune activation in H. pylori infection. Elevated NLR has been correlated with more severe mucosal injury and delayed recovery following eradication therapy[37,38]. Although NLR was not assessed in this study, incorporating it into future trials could help identify patients with heightened inflammatory responses who may require closer monitoring or extended follow-up. Patients receiving VPZ-AMO therapy should also avoid alcohol and spicy foods to reduce gastric irritation, and probiotics may help mitigate antibiotic-related gastrointestinal symptoms and support adherence. For those with peptic ulcer disease, adjunctive mucosal-protective therapy may accelerate ulcer healing and improve overall treatment outcomes.

Future research should incorporate these biological and clinical parameters in combination with pharmacogenomic profiling (e.g., CYP3A4 and CYP2C19 polymorphisms) and therapeutic drug monitoring to optimize individualized dosing strategies based on host metabolism and acid-suppressive capacity[39].

CONCLUSION

The combination of VPZ with AMO is safe and highly effective for the eradication of H. pylori. All three dosing regimens achieved high eradication rates, with the 0.5 g QID strategy offering the most favorable balance of efficacy, symptom relief, and tolerability. These results support the 0.5 g QID regimen as a practical first-line strategy for H. pylori eradication in high-prevalence regions.