Levofloxacin-based concomitant versus sequential therapy for Helicobacter pylori eradication in treatment-naïve Syrian patients: a randomized trial showing no superiority of sequential therapy

Abstract

Background

Helicobacter pylori (H. pylori) infection remains highly prevalent worldwide, including the Eastern Mediterranean region. In Syria, standard triple therapy effectiveness has declined due to increasing antibiotic resistance, misuse, and healthcare limitations. As susceptibility-guided therapy and recommended regimens may be unavailable, empirical levofloxacin-based therapies remain used. This randomized trial compared two levofloxacin-based regimens under local conditions, as sequential therapy has not been evaluated previously in Syrian patients.

Methods

This single-center, prospective, open-label, randomized superiority trial included 150 treatment-naïve adults with histologically confirmed H. pylori infection. Participants were assigned equally to receive either a 14-day levofloxacin-based concomitant regimen or a 14-day levofloxacin-based sequential regimen. The primary outcome was eradication success, confirmed by negative stool antigen testing 6 weeks after therapy and analyzed using intention-to-treat analysis. Treatment-related adverse events were recorded.

Results

Intention-to-treat eradication rates were 84%(63/75) with concomitant therapy and 81.3%(61/75) with sequential therapy. The risk difference was 2.7% points (95%CI:−9.4 to 14.8), with no significant difference between groups (p = 0.83;OR = 1.20(95% CI:0.516–2.81). Baseline characteristics were comparable. Both regimens were generally well tolerated. Nausea was the most frequent adverse event, followed by anorexia, headache, bitter taste, and skin rash, with no significant difference in adverse event frequency.

Conclusion

Levofloxacin-based sequential therapy was not superior to concomitant therapy for eradication in treatment-naïve Syrian patients. The lack of a statistically significant difference does not establish equivalence or non-inferiority. Both regimens showed moderate effectiveness. When levofloxacin-based therapy is required due to limited alternatives, the simpler concomitant regimen may offer practical advantages. These findings should be interpreted considering local resistance patterns and healthcare limitations, with further multi-center studies incorporating susceptibility testing needed.

Clinical trial registration

ClinicalTrials.gov (NCT06065267), prospectively registered on October 3, 2023.

Supplementary Information

The online version contains supplementary material available at https://doi.org/10.1186/s13099-026-00881-x.

Background

Helicobacter pylori (H. pylori) infection continues to pose a significant global health issue, with the Eastern Mediterranean region experiencing particularly high prevalence rates, reported to be between 22% and 87.6% [1]. While comprehensive epidemiological data from Syria are scarce, research involving Syrian refugees has suggested an H. pylori prevalence of around 34% [2, 3]. Chronic infection with H. pylori is recognized as a class I carcinogen and is linked to a wide range of gastric conditions, such as peptic ulcer disease, gastric adenocarcinoma, mucosa-associated lymphoid tissue (MALT) lymphoma, and unexplained iron deficiency anemia [4–10]. Consequently, eliminating H. pylori is crucial for resolving these diseases and lowering the long-term risk of developing gastric cancer.

Eradication of H. pylori infection has become more challenging globally due to the growing issue of antibiotic resistance [11, 12]. In Syria, the effectiveness of clarithromycin-based triple therapy and other fluoroquinolone-containing regimens has declined [13]. Local pilot studies have shown eradication rates falling below 30% [14]. This decline is probably caused by the extensive, uncontrolled use of antibiotics and the collapse of healthcare systems after years of humanitarian crisis.

Current international guidelines increasingly emphasize the use of bismuth-containing quadruple therapy or susceptibility-guided approaches in regions with high antibiotic resistance. Levofloxacin-containing regimens are generally limited by increasing fluoroquinolone resistance and are not universally recommended as empirical first-line therapy [11, 12]. However, in some settings, including regions with limited access to alternative regimens or locally generated supporting evidence, levofloxacin-based therapies may remain clinically relevant as empirical alternatives.

In Syria, a prior study found that a 14-day levofloxacin-based concomitant regimen achieved an eradication rate of 82.05% [15]. This previous study provided local experience with levofloxacin-based therapy but did not establish superiority of the levofloxacin regimen over the comparator therapy. In addition, contemporary Syrian antimicrobial-resistance surveillance remains limited, and treatment selection may be influenced by restricted access to susceptibility-guided therapy and other guideline-preferred regimens. Levofloxacin was therefore selected for the present trial as a locally relevant empirical treatment option with prior Syrian clinical experience, rather than because it is universally recommended as a preferred first-line regimen. The effectiveness of H. pylori regimens varies geographically according to antimicrobial resistance patterns, previous antibiotic exposure, and local treatment practices [11, 16]. Syria presents a distinct clinical environment due to scarce contemporary resistance data, widespread antimicrobial use, systemic healthcare challenges, and limited access to susceptibility-guided therapy and other treatment options. Hence, assessing these specific regimens within the Syrian population yields critical local evidence to determine their empirical effectiveness [17]. Therefore, we conducted a prospective randomized superiority trial to compare a 14-day levofloxacin-based sequential regimen with a 14-day levofloxacin-based concomitant regimen in treatment-naïve Syrian patients.

Methods

Study design and setting

This single-center, prospective, parallel-group, active-controlled, superiority, open-label randomized clinical trial was conducted at the outpatient clinic of Ibn Al-Nafees Hospital in Damascus, Syria. The study used a 1:1 allocation ratio to compare the efficacy of two levofloxacin-based regimens as empirical first-line therapies for H. pylori infection. The trial was prospectively registered on ClinicalTrials.gov (NCT06065267). The detailed study protocol has been published previously [18]. The study flow diagram is presented in Fig. 1 [19].

Fig. 1.

Study flow diagram. The flowchart details recruitment, randomization, treatment completion (or early discontinuation), stool antigen testing at week 6 ± 3 days, and outcome classification for both intention-to-treat (ITT) and per-protocol (PP) analyses. ITT failures are further categorized into confirmed persistent infection (19 participants: 9 in the concomitant group and 10 in the sequential group) and missing test-of-cure (TOC) results (7 participants: 3 and 4, respectively). Among the 15 participants who did not complete therapy, 8 had a TOC result and were cured (counted as ITT successes), while 7 lacked a TOC result (counted as ITT failures)

Participant selection

Participants were recruited from the outpatient clinic of Ibn Al-Nafees Hospital, a Ministry of Health-affiliated medical facility in Damascus, Syria. The hospital serves as a referral center for patients from different regions of the country.

Eligible participants were adults aged 18–65 years who were treatment-naïve for H. pylori infection and had histologically confirmed H. pylori positivity [18].

Participants were excluded if they met any of the following criteria: (i) known allergy to any study medication; (ii) pregnancy or lactation; (iii) serious systemic illness, including severe cardiopulmonary or hepatic dysfunction, chronic renal failure, or a history of gastric cancer or gastrectomy; (iv) refusal to participate; or (v) ongoing use of non-steroidal anti-inflammatory drugs (NSAIDs), antibiotics, proton-pump inhibitors (PPIs), H2 receptor antagonists, aspirin, herbal products, or probiotics during the study period [18].

Randomization, allocation concealment, and blinding

Using a computer-generated randomization sequence developed in R [20], participants were allocated to one of the two treatment groups in a 1:1 ratio. An allocation list was predetermined, ensuring equal distribution with 75 participants in each group, and was randomly shuffled using a uniform random number function. An independent assistant, who did not participate in recruiting participants, administering treatments, or assessing outcomes, prepared the final sequence [18].

To guarantee allocation concealment, opaque, sealed envelopes with sequential numbering were used. These envelopes held the treatment assignments and were only opened once informed consent had been secured and the baseline assessment finished, thus preventing any prior knowledge of the allocation [18].

The trial was conducted as open-label since it was impractical to blind participants and treating physicians due to the distinct treatment regimens. Nevertheless, the assessment of outcomes and the analysis of data were conducted in a blinded manner. Laboratory staff responsible for stool antigen testing, along with data collectors and analysts, were kept unaware of the treatment allocations. Outcome assessment forms did not contain treatment assignments, and data collectors were advised against inquiring about participants’ assigned regimens [18].

Interventions

H. pylori infection was verified via histological examination of gastric samples. Five biopsy samples were collected using the Sydney system and examined using hematoxylin and eosin and Giemsa staining [21]. Participants received one of the following 14-day treatment regimens:

Levofloxacin-based concomitant regimen: 500 mg once daily, 1000 mg amoxicillin, 500 mg tinidazole, and 20 mg esomeprazole twice daily for 14 days [11, 12, 15].

Levofloxacin-based sequential regimen: esomeprazole 20 mg and amoxicillin 1000 mg twice daily on days 1–7, then metronidazole 500 mg, esomeprazole 20 mg twice daily, and levofloxacin 500 mg once daily on days 8–14 [11, 12, 15].

Face-to-face counseling, written informational pamphlets, and biweekly reminder messages all helped increase treatment adherence [18].

Outcome measures

The primary outcome was H. pylori eradication, defined as a negative stool antigen test using the enzyme immunoassay (EIA) method performed 6 weeks (± 3 days) after completion of therapy [22]. Participants were instructed to avoid proton pump inhibitors (PPIs), antibiotics, bismuth compounds, and other restricted medications for at least 6 weeks before testing to reduce the risk of false-negative results.

The primary analysis followed the intention-to-treat (ITT) principle, including all randomized participants according to their assigned treatment group regardless of adherence, protocol deviations, or withdrawal. Participants with missing outcome data, loss to follow-up, or premature discontinuation were considered treatment failures [23].

Secondary outcomes included safety assessment based on the type and frequency of adverse events and treatment adherence, assessed by pill count within 3 days after completion of therapy. Treatment completion was defined as consumption of the prescribed regimen according to the study protocol.

Statistical analysis

Categorical variables were evaluated using Fisher’s exact test when suitable [24]. The Shapiro-Wilk test was used to determine distributional normality in continuous data [25]. Welch’s t-test was used to compare regularly distributed variables, whereas the Mann-Whitney U test was used for non-normally distributed variables [26]. Statistical significance was determined as p < 0.05. Eradication rates were given using two-sided 95% confidence intervals (CIs) [27].

Data were managed using LibreOffice Base 26.2 [28], which included double-entry verification and validation mechanisms. Statistical analyses were carried out using R version 4.5.3 [20].

Sample size calculation

The sample size was calculated based on the primary outcome of H. pylori eradication rate analyzed according to the intention-to-treat (ITT) principle. Assuming eradication rates of 82.05% for the levofloxacin-based concomitant regimen (P₁), based on previous local clinical data, and 87.8% for the levofloxacin-based sequential regimen (P₂), the calculation was performed using a 1:1 allocation ratio (K = 1). The trial was designed to detect a clinically relevant absolute difference of 10% points favoring sequential therapy, with 80% power (β = 0.20; Z_β = 0.845) and two side significance level of 5% (α = 0.05; Zα = 1.96) [18, 29, 30].

Using the formula for a two-group parallel superiority trial, the required sample size was calculated as 64 participants per group. After accounting for an anticipated 15% dropout rate, the final target sample size was set at 150 participants.

The trial was designed as a superiority study and was not powered to demonstrate equivalence or non-inferiority between treatment groups. Therefore, failure to detect a statistically significant difference should be interpreted as absence of demonstrated superiority of sequential therapy rather than evidence that the two regimens have equivalent efficacy.

Results

Baseline characteristics

The baseline demographic and clinical characteristics are described in Table 1. A total of 150 randomized participants were included in the ITT analysis. Age was not normally distributed (Shapiro-Wilk test: W = 0.959, p < 0.001), therefore continuous data were summed using non-parametric techniques. The median age was 38 (IQR: 23), with a range of 17 to 64 years. The age distribution was not significantly different between the Levofloxacin-Concomitant and Levofloxacin-Sequential groups (Mann-Whitney U = 2770, p = 0.873; rank biserial correlation = 0.0153).

Table 1.

The baseline demographic and clinical characteristics

Variable	Concomitant n (%)	Sequential n (%)	Fisher’s Exact p	OR	95% CI
Eradication rate	63/75 (84%)	61/75 (81.3%)	0.83	1.2	0.516–2.81
Sex (Female)	39/75 (52%)	43/75 (57.3%)	0.623	0.806	0.423–1.53
Smoking	31/75 (41.3%)	30/75 (40.0%)	1	0.95	0.49–1.82
Alcohol consumption	2/75 (2.7%)	2/75 (2.7%)	1	1	0.137–7.29
Anorexia	7/75 (9.3%)	6/75 (8%)	1	0.845	0.270–2.64
Nausea	17/75 (22.7%)	9/75 (12%)	0.13	0.465	0.193–1.12
Headache	2/75 (2.7%)	6/75 (8%)	0.276	3.17	0.620–16.3
Skin rash	1/75 (1.3%)	1/75 (1.3%)	1	1	0.0614–16.3
Bitter taste	4/75 (5.3%)	4/75 (5.3%)	1	1	0.241–4.16

OR: odds ratio

CI: confidence interval

Baseline demographic and clinical characteristics were balanced between groups, such as gender distribution (52.0% vs. 57.3% female, p = 0.623), smoking status (41.3% vs. 40%, p = 1), alcohol intake (2.7% vs. 2.7%, p = 1), and anorexia (9.3% vs. 8%, p = 1). These findings indicate adequate baseline comparability between the two randomized groups.

Treatment adherence

Treatment adherence was assessed using pill counts after completion of therapy. Overall, 135 of 150 randomized participants (90%) completed the prescribed treatment course. No clinically meaningful differences in treatment completion were observed between the levofloxacin-based concomitant (69/75, 92%) and sequential (66/75, 88%) groups. Importantly, treatment non-completion by itself did not equate to treatment failure: among the 15 participants who did not complete therapy, 8 (3 in the concomitant group and 5 in the sequential group) still provided a stool sample at week 6 and were confirmed eradicated; these 8 are included in the ITT analysis as successes but were appropriately excluded from the per-protocol analysis. The remaining 7 non-completers (3 and 4, respectively) had no documented test of cure (TOC) result and are classified as ITT failures due to missing TOC. The potential influence of treatment complexity on adherence was considered, particularly because the sequential regimen required a transition between antibiotic phases.

Primary outcome

Of the 150 randomized participants, 135 (90.0%) completed the prescribed treatment course and were included in the per-protocol (PP) analysis: 69/75 (92.0%) in the levofloxacin-based concomitant group and 66/75 (88.0%) in the levofloxacin-based sequential group. Accordingly, 6 participants in the concomitant group and 9 in the sequential group did not complete the course. All 150 randomized participants were retained in the intention-to-treat (ITT) analysis, with missing outcome data, loss to follow-up, or premature discontinuation classified as treatment failures per the prespecified plan. In the ITT analysis, the primary outcome was H. pylori eradication rate and was achieved in 63/75 (84.0%) participants in the levofloxacin-based concomitant group and 61/75 (81.3%) participants in the levofloxacin-based sequential group. Fisher’s exact test showed no statistically significant difference between the groups (p = 0.83). The odds ratio for eradication (concomitant versus sequential therapy) was 1.20 (95% CI: 0.516–2.81), with the confidence interval including the null value. The absolute risk difference was 2.7% points (95% CI: −9.4 to 14.8), favouring the concomitant regimen.

To provide a granular accounting of the 26 ITT failures, we categorized them by outcome. In the concomitant group (12 failures), 9 were due to confirmed persistent infection (based on positive stool antigen testing among treatment completers) and 3 were due to missing test-of-cure (TOC) results. In the sequential group (14 failures), 10 were due to persistent infection and 4 were due to missing TOC results. Overall, the 26 ITT failures consisted of 19 confirmed persistent infections and 7 missing TOC results. No other reasons accounted for ITT failure.

In the per-protocol analysis, including only participants who completed the assigned treatment course, eradication was achieved in 60/69 (87.0%) participants in the levofloxacin-based concomitant group and 56/66 (84.8%) participants in the levofloxacin-based sequential group. The absolute risk difference in the per-protocol population was 2.1% points (95% CI: -9.6 to 13.9), with no statistically significant difference between groups. These findings were consistent with the primary intention-to-treat analysis. Table 2: Primary and per-protocol eradication outcomes.

Table 2.

Intention-to-treat and per-protocol analyses of Helicobacter pylori eradication outcomes

Analysis	Concomitant n (%)	Sequential n (%)	Fisher’s Exact p	OR	95% CI	Risk Difference (95% CI)
ITT	63/75 (84.0%)	61/75 (81.3%)	0.83	1.20	0.516–2.81	+ 2.7% (− 9.4 to 14.8)
PP	60/69 (87.0%)	56/66 (84.8%)	0.81	1.19	0.50–2.84	+ 2.1% (− 9.6 to 13.9)

ITT: Intention-to-treat

PP : per-protocol analyses

OR: odds ratio

CI: confidence interval

Because this trial was designed to evaluate superiority rather than equivalence or non-inferiority, the absence of a statistically significant difference should be interpreted as failure to demonstrate superiority of sequential therapy over concomitant therapy and should not be considered evidence that the two regimens have equivalent efficacy.

Treatment indications

The clinical reasons for administering H. pylori eradication therapy were similar across the two treatment groups, as shown in Table 3. Dyspepsia emerged as the most common reason in both the Levofloxacin-Concomitant group (41 out of 75, 54.7%; 95% CI: 43.4–65.4) and the Levofloxacin-Sequential group (43 out of 75, 57.3%; 95% CI: 46.1–67.9). This was followed by active peptic ulcer and unexplained iron deficiency anemia. Less frequent reasons included endoscopic removal of early gastric cancer, prolonged use of NSAIDs or low-dose aspirin, and MALT lymphoma. Overall, dyspepsia represented more than half of all indications (84 out of 150, 56%; 95% CI: 48-63.7). Fisher’s exact test indicated no statistically significant difference in the distribution of treatment indications between the two groups (p = 0.644), demonstrating that the groups were well-matched regarding the clinical indications for therapy.

Table 3.

H. Pylori treatment indications

Treatment Indication	Concomitant n (%)	Concomitant 95% CI	Sequential n (%)	Sequential 95% CI	Total n (%)	Total 95% CI
Dyspepsia	41 (54.7)	43.4–65.4	43 (57.3)	46.1–67.9	84 (56)	48–63.7
Active peptic ulcer	16 (21.3)	13.6–31.9	16 (21.3)	13.6–31.9	32 (21.3)	15.5–28.6
Unexplained iron deficiency anemia	13 (17.3)	10.4–27.4	9 (12)	6.4–21.3	22 (14.7)	9.9–21.2
Endoscopic resection of early gastric cancer (EGC)	1 (1.3)	0.2–7.2	4 (5.3)	2.1–12.9	5 (3.3)	1.4–7.6
Long term NSAID use	1 (1.3)	0.2–7.2	2 (2.7)	0.7–9.2	3 (2)	0.7–5.7
Long term low-dose aspirin use	2 (2.7)	0.7–9.2	1 (1.3)	0.2–7.2	3 (2)	0.7–5.7
MALT lymphoma	1 (1.3)	0.2–7.2	0 (0)	0.0–4.9	1 (0.7)	0.1–3.7

Safety outcomes

Adverse events were mild and occurred at similar frequencies in both treatment groups, with complete safety data available for all participants (Table 1). Nausea was the most commonly reported adverse event, occurring in 17/75 participants (22.7%) in the Levofloxacin-Concomitant group and 9/75 participants (12%) in the Levofloxacin-Sequential group; however, the difference was not statistically significant (Fisher’s exact test, p = 0.13).

Other reported adverse events included headache (2.7% vs. 8%, p = 0.276), skin rash (1.3% vs. 1.3%, p = 1), bitter taste (5.3% vs. 5.3%, p = 1), and anorexia (9.3% vs. 8%, p = 1). No significant differences in adverse events were observed between groups, and both regimens demonstrated comparable tolerability. No serious adverse events occurred, and no participant discontinued treatment because of adverse events.

Discussion

This randomized clinical trial evaluated whether a 14-day levofloxacin-based sequential regimen was superior to a 14-day levofloxacin-based concomitant regimen for empirical first-line eradication therapy of H. pylori infection in treatment-naïve Syrian patients. Contrary to our hypothesis, sequential therapy did not achieve a higher eradication rate than concomitant therapy. The intention-to-treat eradication rates were 81.3% (61/75) in the sequential group and 84% (63/75) in the concomitant group, with no statistically significant difference between regimens (Fisher’s exact test, p = 0.83; OR = 1.2, 95% CI: 0.516–2.81). Both regimens demonstrated comparable observed safety profiles, with nausea being the most frequently reported adverse event, followed by headache, anorexia, bitter taste, and skin rash. No statistically significant differences in adverse events were observed between the groups. However, the trial was designed to evaluate the superiority of sequential therapy; therefore, the results should be interpreted as a failure to demonstrate superiority rather than as evidence of equivalent efficacy or safety.

Our findings differ from previous meta-analytic evidence suggesting that levofloxacin-based sequential therapy may achieve higher eradication rates, approximately 87.8%, compared with concomitant regimens [17]. Several factors may contribute to this discrepancy. Differences in local antimicrobial resistance patterns may have contributed to reduced treatment effectiveness; however, this cannot be confirmed because susceptibility testing was not performed. The Syrian healthcare context, characterized by widespread antibiotic misuse, over-the-counter antibiotic availability, and healthcare infrastructure deterioration, may have further influenced treatment effectiveness [13, 31–33].

Ideally, levofloxacin-based regimens should be reserved for patients with demonstrated fluoroquinolone susceptibility. The absence of baseline antimicrobial susceptibility testing limits the ability to determine whether specific resistance patterns contributed to treatment failure. Post-treatment confirmation of eradication remains important regardless of the regimen used, particularly when empirical therapy is selected in settings with limited susceptibility information. Continued local antimicrobial-resistance surveillance is also needed to inform empirical treatment decisions and to determine whether levofloxacin-based regimens remain appropriate in the local setting. Therefore, the observed eradication rates should be interpreted as empirical effectiveness estimates within this clinical setting rather than as direct measures of regimen performance independent of resistance mechanisms.

The sequential regimen also requires a mid-treatment antibiotic transition, which may introduce additional challenges for adherence compared with the simpler concomitant regimen. Although adherence was encouraged through education and reminders, the complexity of sequential therapy may be less suitable in real-world settings where medication continuity and follow-up can be challenging. These factors may partially explain why a theoretically more targeted regimen did not demonstrate improved efficacy in this population.

Importantly, both regimens achieved eradication rates exceeding 80%; however, the observed efficacy remains below the ideal eradication rates currently sought for empirical first-line therapy [11]. The eradication rate observed with the concomitant regimen (84%) was comparable to previous Syrian data reporting an 82.05% eradication rate with the same protocol, providing additional local evidence regarding its observed effectiveness in this setting [15].

In this Syrian cohort, neither regimen demonstrated a clear efficacy advantage over the other. These findings should not be interpreted as establishing either regimen as the preferred first-line therapy, particularly in the context of increasing fluoroquinolone resistance. However, in settings where levofloxacin-based regimens are selected because of local circumstances, drug availability, or regional evidence, the simpler concomitant regimen may offer practical advantages. Given the absence of a statistically significant difference in observed efficacy and the comparable safety profile, practical considerations such as cost, drug availability, patient preference, and the likelihood of adherence may inform treatment selection only after an appropriate, resistance-consistent eradication strategy has been identified. In settings where preferred regimens or susceptibility-guided therapy are not accessible, a levofloxacin-based regimen may be considered only as a carefully qualified empirical alternative, taking into account local resistance patterns and the limitations of the available evidence. Susceptibility-guided therapy is preferred where available. In resource-limited or conflict-affected settings, the concomitant regimen may further reduce the risk of dosing errors by avoiding the antibiotic switching required with sequential therapy.

The findings should be interpreted within the context of limited availability of susceptibility-guided therapy and should not be extrapolated to settings where resistance-guided or guideline-preferred regimens are readily accessible.

The strengths of this study include its prospective randomized design, robust allocation concealment using sequentially numbered opaque sealed envelopes, blinded outcome assessment by laboratory personnel and data analysts, intention-to-treat analysis with conservative handling of missing data, prospective trial registration, and rigorous data management procedures, including double-entry data verification [19].

Several limitations should be considered. The single-center design in Damascus may limit the generalizability of the findings to other regions of Syria with different antimicrobial resistance patterns or healthcare conditions. The open-label design, necessitated by differences in treatment regimens, may have introduced performance bias; however, blinding of laboratory personnel and data analysts minimized the risk of detection and analysis bias. The absence of baseline antimicrobial susceptibility testing precluded assessment of the effect of specific resistance patterns on treatment outcomes. Eradication was assessed using stool antigen testing alone, without confirmation by a second diagnostic method, which may have introduced some diagnostic variability. The six-week follow-up period did not permit evaluation of long-term recurrence or reinfection. Finally, the humanitarian crisis and healthcare constraints in Syria may have influenced treatment delivery and limit the direct generalizability of these findings to more stable healthcare systems.

Although treatment adherence was generally high, the absence of antimicrobial susceptibility testing prevented evaluation of the relationship between specific resistance mechanisms and eradication failure. In addition, the sample size was calculated to detect superiority and was not designed to demonstrate equivalence or non-inferiority. Therefore, the absence of a statistically significant difference should be interpreted as failure to demonstrate superiority rather than evidence of equivalent efficacy. Larger multicenter studies incorporating antimicrobial resistance profiling are needed to determine whether either regimen offers clinically meaningful advantages.

Future multicenter studies including larger and more geographically diverse Syrian populations, routine antimicrobial susceptibility testing, and direct comparisons with bismuth-based quadruple therapy are warranted to optimize empirical H. pylori treatment strategies in high-resistance settings.

Conclusion

In this randomized superiority trial among treatment-naïve Syrian patients, a 14-day levofloxacin-based sequential regimen did not demonstrate superiority over a 14-day levofloxacin-based concomitant regimen for H. pylori eradication. These findings should be interpreted within the limitations of a superiority trial that was not powered to establish equivalence or non-inferiority. The study provides locally relevant comparative evidence in a setting characterized by antibiotic resistance and healthcare limitations, but the results should not be interpreted as proof of equivalence or non-inferiority. Further multicenter studies incorporating antimicrobial susceptibility testing are required to optimize locally appropriate eradication strategies in Syria.

Supplementary Information

Below is the link to the electronic supplementary material.

Abbreviations

CI

Confidence interval

CONSORT

Consolidated Standards of Reporting Trials

EIA

Enzyme immunoassay

H. pylori

Helicobacter pylori

IQR

Interquartile range

ITT

Intention-to-treat

MALT

Mucosa-associated lymphoid tissue

NSAIDs

Non-steroidal anti-inflammatory drugs

OR

Odds ratio

PP

Per-protocol

PPI

Proton pump inhibitor

SD

Standard deviation

U test

Mann-Whitney U test

Biographies

Gastroenterologist and Clinical Researcher

Marouf Alhalabi, MD, is a gastroenterologist with clinical and academic interests in gastrointestinal endoscopy, inflammatory bowel disease, and liver diseases. His research focuses on inflammatory bowel diseases, systematic reviews, meta-analyses, and the critical appraisal of medical evidence, with particular interest in evaluating the methodological quality, credibility, and clinical interpretation of evidence in gastroenterology.

Gastroenterologist and Clinical Researcher

Hussam Aldeen Alshiekh, MD, is a gastroenterologist with clinical and academic interests in gastrointestinal endoscopy, inflammatory bowel disease, and hepatology. His academic interests include clinical gastroenterology and research in inflammatory bowel disease and related gastrointestinal and liver disorders.

Author contributions

MA: Conceptualization; Data curation; Methodology; Project administration; Supervision; Writing - original draft; Writing - review & editing. HA: Writing - original draft; Writing - review & editing. AS Alhara: Data collection; Data entry; Writing - review & editing. WS: Data collection; Data entry; Writing - review & editing. All authors have read and agreed to the final version of the manuscript.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Data availability

All data generated and analyzed during this Clinical Trial are included in this article and its supplementary information files.

Declarations

Ethics approval and consent to participate

All methods were carried out in accordance with relevant guidelines and regulations. Damascus Hospital and the Ibn Al-Nafees Ethics Committee reviewed and approved this study (No: 41/23).

Conflict of interest

The authors declare that they have no competing interests. Specifically, none of the authors have any financial or personal relationships that could inappropriately influence or bias the work presented in this manuscript. This includes employment, consultancies, stock ownership, honoraria, paid expert testimony, patent applications or registrations, grants or other funding, and editorial or advisory board affiliations with this journal.

Competing interests

The authors declare no competing interests.