Low-dose vs standard-dose minocycline in bismuth quadruple therapy for first-line Helicobacter pylori eradication: A randomized controlled, noninferiority trial

Abstract

BACKGROUND

Bismuth-containing quadruple therapy (BQT) is a proven first-line therapy against Helicobacter pylori (H. pylori) infection. Minocycline has been progressively employed as a possible alternative in clinical practice to tetracycline; nevertheless, the optimum dosing of minocycline in BQT is not well understood.

AIM

To compare the noninferiority of a low dose (50 mg) minocycline-based BQT with the standard dose (100 mg) regimen in treatment-naive patients.

METHODS

This was a noninferiority, prospective, randomized, controlled trial that recruited treatment-naive Chinese patients suffering from H. pylori infection. Moreover, the participants were randomly allocated (1:1) to either a low-dose experimental regimen (rabeprazole sodium enteric-coated capsules 20 mg, compound bismuth aluminate granules 2.6 g, amoxicillin 1000 mg, and minocycline 50 mg, all at a dose of 2 times a day) or a standard-dose control regimen (the same components except minocycline 100 mg, 2 times a day). A standardized mucosal healing period was then administered to patients with concomitant peptic ulcers. The main outcome measure was the eradication rate of H. pylori, which was measured by the ¹³C-urea breath test. Secondary endpoints included incidence of treatment compliance, adverse events (AEs), peptic ulcer healing rate, and cost-effectiveness.

RESULTS

The intention-to-treat analysis indicated that the H. pylori eradication rates were 84.2% and 87.5% in the low-dose and standard-dose groups (risk difference: -3.3%; 95%CI: -10.7% to 4.1%; P = 0.459). The per-protocol (PP) analysis yielded consistent results (91.0% vs 92.9%; risk difference: -1.9%; 95%CI: -7.9% to 4.1%; P = 0.595). The PP analysis showed that the low-dose regimen was not inferior (P = 0.013). It is important to note that the low-dose group had a much better safety profile, and the AEs were less frequent (18.3% vs 32.5%; P = 0.012). No substantial variances were noted in treatment compliance (98.3% vs 97.5%; P = 1.000) or ulcer healing rate (88.0% vs 85.2%; P = 1.000). The cost-effectiveness ratio was less in the low-dose group (3.54 vs 4.34).

CONCLUSION

BQT using low doses of minocycline has high eradication efficacy of H. pylori with fewer AEs and better cost-effectiveness, which justifies its expanded clinical application.

Key Words: Minocycline; Low-dose; Helicobacter pylori; Eradication therapy; Adverse events

Core Tip: The optimal dose of minocycline in bismuth-containing quadruple therapy remains uncertain. This study demonstrates that a low-dose minocycline-based regimen is noninferior to the standard-dose regimen in treatment-naïve Helicobacter pylori infection, while offering a superior safety profile and better cost-effectiveness, supporting its clinical utility.

INTRODUCTION

Helicobacter pylori (H. pylori) infection is commonly known as one of the most significant health problems around the world and the leading etiological agent of peptic ulcer disease, gastric cancer, and chronic gastritis[1-3]. National and international consensus statements highlight the need to enhance first-line eradication rates, which can help to decrease healthcare expenses, curb the emergence of antibiotic resistance, reduce adverse events (AEs), and improve patient compliance[4-7].

As the problem of antibiotic resistance is on the rise, the H. pylori eradication rates have reduced[3,8-11]. In China, clarithromycin, levofloxacin, and metronidazole resistance have been increasing over the past few years[8,12]. As a result, regimens based on amoxicillin- and tetracycline-based regimens have become more popular. The most recent guidelines suggest the utilization of bismuth-containing quadruple therapy (BQT) as first-line therapy against H. pylori infection, with tetracycline as part of two of five recommended regimens[6]. Nonetheless, tetracycline is limited in its clinical application due to its limited availability. Minocycline is a semi-synthetic derivative of tetracycline, which has a similar antibacterial spectrum as tetracycline and has better oral bioavailability because of almost complete absorption[3,8-11]. Its gastrointestinal side effects have restricted its extensive clinical use, with a recommended dosage of 100 mg twice a day[13] being the most commonly recommended.

It is thus crucial to optimize the dose of minocycline to balance between eradication efficacy and patient safety. It is not yet clear whether a 50 mg dose of the drug can be used with the same eradication rates as the standard 100 mg dose as first-line therapy, although low-dose regimens have been adopted in some clinical settings[14]. In line with this, the study was aimed at comparing the safety, cost-effectiveness, and efficacy of these two dosing strategies. We wanted to produce strong clinical evidence to guide the optimization of H. pylori first-line eradication therapy and enhance patient outcomes.

MATERIALS AND METHODS

Study design and ethical issues

It was an open-label, randomized controlled, non-inferiority, and prospective trial in treatment-naive patients suffering from H. pylori infection. Moreover, the outpatient clinic of the Department of Gastroenterology, the Second Hospital of Tianjin Medical University was used to recruit participants between November 15, 2024 and March 15, 2025. This study was approved by the Ethics Committee of the Second Hospital of Tianjin Medical University, No. KY2024K340 and the trial was registered at the Chinese Clinical Trial Registry (www.chictr.org.cn), No. ChiCTR2500100094. All the procedures were done per the Declaration of Helsinki. The research was reported according to the CONSORT guidelines.

Study population

Inclusion criteria: (1) Age 18-75 years; (2) Positive ¹³C-urea breath test (¹³C-UBT), which was described as a delta over baseline 4; (3) No use of bismuth agents, antibiotics, or anti-H. pylori herbal medicines within 4 weeks before enrollment; and (4) No use of acid-suppressive agents within 2 weeks before enrollment.

Exclusion criteria: (1) Known hypersensitivity to any of the study drugs; (2) Malignancy; (3) Pregnancy, lactation or planned pregnancy during the study period; (4) Complications of peptic ulcer disease (e.g., active massive hemorrhage); (5) Severe hepatic or renal dysfunction; (6) Severe cardiovascular, pulmonary or hematological disease; (7) Previous gastric surgery; and (8) Gastrinoma.

Randomization and interventions

The participants were randomly allocated in a 1:1 proportion to the low-dose or standard-dose group. An independent research assistant created the randomization sequence with a computer-generated random number table with a fixed block size of 10. The block size was blinded to investigators who enrolled patients. Sequentially numbered, opaque, sealed envelopes were made and preserved by the same independent research assistant to ensure allocation concealment. Investigators opened the envelopes sequentially after enrollment to allocate participants to their groups. Since it was an open-label study, treating physicians and participants were not blinded to treatment assignment. Nevertheless, the technician who did the ¹³C-UBT was not blinded to group assignment.

Sample size calculation

With an assumed eradication rate of 89.9% in the low-dose group and 90.0% in the standard-dose group[15-17], a non-inferiority margin of 10%, a one-sided type I error α (0.05) and a type II error β (0.2; power = 80%), and a 1:1 allocation ratio, the required sample size was 114 patients per group. The estimation of the sample size was done with PASS version 15.0 (NCSS LLC, UT, United States). Allowing for a 5% loss to follow-up, the minimum required sample size was raised to 120 patients per group. The 254 patients were first screened; 14 were not included because they were not meeting the inclusion criteria or refused to participate. The rest of the 240 eligible patients were then randomized.

Treatment regimens

Patients were randomly categorized into 2 groups. The low-dose group (n = 120) was given rabeprazole sodium enteric-coated capsules (20 mg), compound bismuth aluminate granules (2.6 g), amoxicillin (1000 mg), and minocycline (50 mg) twice a day. The standard-dose group (n = 120) was given rabeprazole sodium enteric-coated capsules (20 mg), compound bismuth aluminate granules (2.6 g), amoxicillin (1000 mg), and minocycline (100 mg) twice a day.

Procedures

The duration of eradication therapy of H. pylori was 14 days in both groups. All patients were recommended to quit smoking and alcohol use and reduce the consumption of sweets, spicy foods, and other gastric irritants during the treatment period. Patients with gastric or duodenal ulcers diagnosed by esophagogastroscopy were given a 4-week mucosal healing regimen of rabeprazole sodium enteric-coated capsules (20 mg once daily) and rebamipide (0.1 g, three times daily) 2 weeks after eradication therapy. Follow-up esophagogastroscopy was done after 6 weeks of treatment to determine the healing of ulcers and the ¹³C-UBT was done 2 weeks after the drug was stopped. In patients who did not have peptic ulcers, the ¹³C-UBT was done 4 weeks after the eradication therapy. Moreover, effective H. pylori eradication was described as a negative outcome of the use of the ¹³C-UBT. Discontinuation of treatment was done under the following circumstances: (1) Severe AEs during treatment; or (2) Medical conditions that preclude the continuation of treatment.

Follow-up of patients was done through telephone and outpatient visits on day 7 and 14 of treatment initiation. At each follow-up, medication adherence and AEs were systematically recorded. A follow-up esophagogastroscopy was conducted 6 weeks after treatment in peptic ulcers patients to determine the healing of ulcers.

Outcome measures

The main outcome was the rate of eradication of H. pylori. Moreover, secondary outcomes were the rate of healing of peptic ulcers, AEs and their incidence and severity, adherence to treatment, and cost-effectiveness.

H. pylori eradication rate: Described as a negative ¹³C-UBT outcome.

Peptic ulcer healing rate: The healing of ulcers was measured using esophagogastroscopy and was categorized as follows: Complete healing (complete disappearance of the ulcer), marked healing (> 80% reduction in ulcer area), partial healing (> 50% reduction), and non-healing (≤ 50% reduction). The rate of healing of the ulcers was computed as: (Total number of patients with confirmed ulcers - number of patients with non-healing ulcers)/total number of patients with confirmed ulcers × 100%.

AEs and compliance: AEs were anorexia, nausea, vomiting, diarrhea, bloating, rash, dizziness, and other symptoms related to the treatment. They were compared in terms of incidence, severity grading, and discontinuation of treatment. Mild AEs did not have any substantial effect on daily life, moderate AEs led to some restriction of daily activities, and severe AEs severely affected daily functioning and frequently required discontinuation of treatment. Treatment compliance was determined as the ratio of the medication that was prescribed and taken. A compliance rate of ≥ 80% was considered acceptable.

Cost-effectiveness ratio: Direct medication costs were included; direct costs of follow-up visits, ¹³C-urea breath tests, endoscopic tests, AE management, and other indirect medical costs were not included. Cost was determined as the overall cost of drugs per patient in the 14-day H. pylori eradication therapy. Effectiveness was determined as the rate of H. pylori eradication per-protocol (PP). The cost-effectiveness ratio was determined, and the lower the value the higher the cost-effectiveness.

Statistical analysis

SPSS version 22.0 was used to analyze the baseline demographic characteristics. Continuous variables were represented as mean ± SE, whereas categorical variables were reported as n (%). Prior to analysis, homogeneity of variance and data normality were assessed. In the case of continuous variables, the independent-samples t-test was applied to normally distributed data with equal variances, otherwise the Mann-Whitney U test was applied. Pearson χ² test, Fisher exact test or continuity-corrected χ² test was utilized to compare categorical variables.

SAS version 9.4 was used to conduct noninferiority analysis. All randomized patients were considered the intention-to-treat (ITT) population. Only patients who had both the treatment and follow-up assessments were included in the PP population; patients who discontinued treatment, left the study, or were lost to follow-up were excluded. A one-sided Z-test was used to determine noninferiority and two-sided 95%CI were computed to determine between-group differences. All P values were two-sided except for the noninferiority test. A P value < 0.05 was considered statistically significant.

RESULTS

Baseline characteristics

Figure 1 displays the patient enrolment’s flowchart. Table 1 indicates that there were no significant variances between the two groups regarding baseline demographic or clinical characteristics, such as age, sex, alcohol consumption, smoking history, comorbidities, disease composition, nonsteroidal anti-inflammatory drug use, body mass index, and endoscopic findings (all P > 0.05).

Figure 1 Study flow and enrollment of patients. ITT: Intention-to-treat; PP: Per-protocol.

Table 1 Demographic and clinical data of all patients, n (%).

Variables	Low-dose group (n = 120)	Standard-dose group (n = 120)	P value
Male sex	63 (52.5)	58 (48.3)	0.519
Age (year), mean ± SD	65.4 ± 4.4	66.3 ± 5.0	0.137
Smoking	64 (53.3)	59 (49.2)	0.518
Alcohol	62 (51.7)	60 (50.0)	0.796
Coronary artery disease	56 (46.7)	57 (47.5)	0.897
Diabetes	61 (50.8)	62 (51.7)	0.897
Hypertension	53 (44.2)	54 (45.0)	0.897
Use of NSAIDs	34 (28.3)	30 (25.0)	0.559
BMI (kg/m2), mean ± SD	22.9 ± 2.9	23.5 ± 4.0	0.16
Concomitant peptic ulcers
Gastric ulcer	10	11	0.951
Duodenal ulcer	15	16

BMI: Body mass index; NSAID: Nonsteroidal anti-inflammatory drug.

H. pylori eradication rate

The ITT analysis showed that the H. pylori eradication rates were 84.2% (101/120) and 87.5% (105/120) in the two groups, respectively, with a risk variance of -3.3% (95%CI: -10.7% to 4.1%), and no statistically significant difference (P = 0.459). In the PP analysis, eradication rates were 91.0% (101/111) and 92.9% (105/113), respectively, corresponding to a risk variance of -1.9% (95%CI: -7.9% to 4.1%). Noninferiority analysis showed that the low-dose group was noninferior to the standard-dose group in the PP population (P = 0.013; Table 2).

Table 2 Helicobacter pylori eradication rate between the two groups, % (n/total).

Regimens	Low-dose group	Standard-dose group	P value (difference)	P value (noninferiority)	95%CI
ITT analysis	84.2 (101/120)	87.5 (105/120)	0.459	0.069	-10.7% to 4.1%
PP analysis	91.0 (101/111)	92.9 (105/113)	0.595	0.013a	-7.9% to 4.1%

^aP < 0.05.

ITT: Intention-to-treat; PP: Per-protocol.

AEs and compliances

The incidence of AEs was 18.3% (22/120) in the low-dose group and 32.5% (39/120) in the standard-dose group (P = 0.012). Only mild AEs showed a significant difference, being less common in the low-dose group (P = 0.017), but no variances were noted in moderate or severe events (P > 0.05). There were no substantial variances between the two groups in the type of AEs or the primary causes of treatment discontinuation (P > 0.05). Compliance rates were 98.3% (118/120) and 97.5% (117/120), respectively, with no substantial variance between groups (P = 1.000; Table 3).

Table 3 Adverse events between the two groups, n (%).

Variables	Low-dose group (n = 120)	Standard-dose group (n = 120)	P value
Total	22 (18.3)	39 (32.5)	0.012a
AE grade
Mild	11 (9.2)	24 (20.0)	0.017a
Moderate	5 (4.2)	12 (10.0)	0.078
Severe	6 (5.0)	3 (2.5)	0.497
Main AE
Anorexia	2 (1.7)	5 (4.2)	0.443
Nausea	3 (2.5)	5 (4.2)	0.719
Vomiting	4 (3.3)	5 (4.2)	1.000
Diarrhea	5 (4.2)	6 (5.0)	0.760
Bloating	6 (5.0)	8 (6.7)	0.582
Skin rash	1 (0.8)	5 (4.2)	0.215
Dizziness	1 (0.8)	5 (4.2)	0.215
Discontinued due to AEs
Severe diarrhea	4 (3.3)	1 (0.8)	0.366
Vomiting	2 (1.7)	2 (1.7)	1.000
Personal reasons	2 (1.7)	3 (2.5)	1.000
Compliance	118 (98.3)	117 (97.5)	1.000

^aP < 0.05.

AE: Adverse event.

Ulcer healing rate

The healing rates of ulcers were 88.0% (22/25) in the low-dose group and 85.2% (23/27) in the standard-dose group, and there was no substantial variance between the groups (P = 1.000; Table 4).

Table 4 Ulcer healing rates between the two groups.

Group	Ulcer healing status				Healing rates (%)
	Complete healing	Marked healing	Partial healing	Non- healing
Low-dose group	9	8	5	3	88.0
Standard-dose group	10	8	5	4	85.2
P value	1.000

Cost-effectiveness ratios

The low- and standard-dose groups had cost-effectiveness ratios (direct drug cost/eradication rate) of 3.54 and 4.34, respectively (Table 5).

Table 5 Cost-effectiveness ratios between the two groups.

Group	E (%)	C (CNY)	C/E
Low-dose group (n = 120)	91.0%	321.7	3.54
Standard-dose group (n = 120)	92.9%	402.9	4.34

E: Effectiveness; C: Cost; C/E: Cost-effectiveness ratio.

DISCUSSION

With the increasing resistance to antibiotics[3,18-20], striking a balance between high eradication rates and tolerability to treatment is one of the greatest challenges in the treatment of H. pylori infection. Even though BQT remains a pillar eradication regimen, its clinical efficacy can be compromised by dose-related AEs that negatively impact patient compliance and treatment adherence[4,7,21]. It is against this background that our research shows that low-dose minocycline-based BQT (50 mg twice a day) is not inferior to the traditional 100 mg twice a day dose, and provides a more sophisticated, safer, and less expensive first-line treatment choice.

As a second-generation semi-synthetic tetracycline, minocycline has become a potential alternative to tetracycline in the H. pylori’s eradication[17,22]. Despite its high efficacy against H. pylori[23-25], tetracycline has been progressively restricted in clinical use due to its common adverse effects on the gastrointestinal tract, complicated dosing schedules, and limited availability in most parts of the world[13,26-28]. Conversely, minocycline has a number of pharmacokinetic and pharmacological benefits, such as almost complete oral bioavailability (95%-100%) that is not significantly affected by food consumption, widespread tissue distribution, and retained activity in some tetracycline-resistant strains[13,27]. Consequently, recent clinical recommendations have been more and more supportive of minocycline as a viable substitute in BQT regimens[5,7,21]. Large-scale studies have demonstrated that the normal dose of minocycline of 100 mg twice daily can eradicate over 80% with a tolerable safety profile[14,15,17,22,29]. However, dose-related adverse effects are still a significant clinical issue, especially gastrointestinal intolerance, vestibular dysfunction, including dizziness, and possible teratogenicity. Recent studies have shown that low dose tetracycline (500 mg twice a day) when used as part of quadruple therapy offers the same eradication rates as standard dosing with better treatment tolerability and patient compliance[30-32]. These results present a solid argument to consider dose-reduction approaches in minocycline-based H. pylori eradication regimens due to the close pharmacological and mechanistic similarities between tetracycline and minocycline.

The pharmacokinetic properties of minocycline in the gastric environment contribute to its clinical efficacy of 50 mg twice a day. Minocycline has a high oral bioavailability (> 90%), and it is rapidly absorbed, with peak plasma concentrations achieved about 2 hours after administration (Tmax = approximately 2 hours). Its high distribution (80-114 L) volume suggests a large tissue penetration, with good accumulation in the gastric mucosa. Moreover, its comparatively low clearance (3.42-4.4 L/hour) and prolonged systemic exposure (area under the curve = approximately 48.3 μg·hour/mL) also play a role in its long-lasting antibacterial effect[13,26]. Even though this dosage is more frequently used in long-term dermatological therapy, its application in the H. pylori’s eradication is justified by the low minimum inhibitory concentration of the organism 0.125 μg/mL[20,33]. Recent research has demonstrated that minocycline 50 mg twice a day has the same eradication rates as tetracycline and better patient compliance due to a more desirable safety profile[14]. In line with these findings, our study showed no inferiority of the 50 mg twice-daily regimen compared to the conventional 100 mg dose, which supports the use of a balanced therapeutic approach that reduces dose-related vestibular and gastrointestinal adverse effects without affecting efficacy.

Though high-dose dual therapy has received a new clinical focus due to its good safety profile and better patient compliance[34], its efficacy is usually limited by the acid instability nature of amoxicillin. Inadequate gastric acid inhibition can facilitate the coccoid conversion of H. pylori, thus significantly lowering eradication effectiveness[35]. Moreover, the therapeutic performance of proton pump inhibitor-based dual regimens is frequently impacted by CYP2C19 genetic polymorphisms, leading to the considerable interindividual variability and, in some cases, suboptimal treatment outcomes[36-38]. Conversely, minocycline does not undergo CYP2C19-mediated metabolism and acts as an antibacterial agent by binding to the A-site of the 30S ribosomal subunit, thus preventing bacterial protein synthesis[39]. This quadruple regimen provides a more dependable and consistent treatment option by combining the stable antimicrobial effect of low-dose minocycline with the synergistic effect of bismuth, which successfully overcomes the limitations associated with host genetic variability and pH-dependent declines in drug efficacy.

Our clinical results showed that the low dose minocycline regimen (50 mg twice a day) had a PP eradication rate of 91.0, which was not inferior to the standard 100 mg twice-daily regimen. The predefined noninferiority criterion was not formally met, although a similar trend was noted in the ITT analysis (84.2% vs 87.5%). This difference could be mainly explained by the discontinuation of treatment and loss to follow-up instead of a real decrease in the therapeutic efficacy. This resulted in an increase in the confidence interval, which decreased the statistical power needed to prove non-inferiority. Notably, the similarity in the healing rates of the two groups (both over 85%) indicates that dose reduction does not have a negative impact on the overall treatment of the acid-related peptic disease. Collectively, these results suggest that the 50 mg twice-daily dose is an effective alternative to the standard dose, with similar eradication efficacy and better treatment tolerability.

The main benefit of the low-dose regimen is that it has a better safety profile and is more cost-effective. A 50% reduction in the dose of minocycline resulted in a substantial reduction in the rate of AEs (18.3% vs 32.5%), which was mainly due to decreases in mild vestibular and gastrointestinal side effects. This increased tolerability, along with the high treatment compliance rate (over 97%), justifies the feasibility and acceptability of the regimen in standard clinical practice. Additionally, it’s cheaper cost-effectiveness ratio (3.54 vs 4.34) underscores its economic advantage, which further justifies its broader implementation, especially in resource-limited and high-volume healthcare facilities.

Although these positive results are achieved, the instances of eradication failure should be carefully considered in terms of both host- and pathogen-related factors. Despite the fact that resistance to amoxicillin and minocycline is relatively rare, regional differences in the patterns of antibiotic susceptibility, along with the impact of CYP2C19 genetic polymorphisms on gastric acid suppression, could be the factors that lead to lower treatment efficacy in some patients.

Limitations

There are a number of limitations in this study. To begin with, H. pylori culture, antimicrobial susceptibility testing, and molecular resistance profiling were not done. Consequently, the possible impact of baseline resistance to amoxicillin or minocycline on eradication outcomes was not assessed. Further research that includes extensive susceptibility testing and molecular resistance studies is required to understand the effect of antibiotic resistance on the effectiveness of treatment. Second, the study was a single-center study, which was carried out in China only, and this could restrict the generalizability of the results, especially considering the high geographic difference in the patterns of H. pylori antibiotic resistance. Multicenter, large-scale studies with various populations and healthcare settings are thus justified to confirm these findings. Third, the open-label design could have created reporting bias, particularly in subjective outcomes like AEs and adherence to treatment. Even though the assessors who conducted the ¹³C-UBT were not aware of the treatment assignment, the possibility of the participant and investigator awareness cannot be fully ruled out. Lastly, there was no direct head-to-head comparison of minocycline-based and tetracycline-based BQT. However, the PP populations of both groups had eradication rates over 90% and both regimens demonstrated clinically acceptable efficacy and could be considered as a possible option in routine clinical practice.

CONCLUSION

Overall, our results are a good indication that low-dose minocycline-based BQT is an effective, well-tolerated, and cost-effective first-line treatment of H. pylori eradication. Moreover, this regimen provides a feasible and balanced treatment method, which justifies its wider use in everyday clinical practice.

ACKNOWLEDGEMENTS

We thank our colleagues in the Second Hospital of Tianjin Medical University for their guidance and strong support throughout this research and manuscript preparation.