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NCT Number: NCT07720232

Bacillus Subtilis and Enterococcus Faecium Probiotic Plus Lipid-Lowering Therapy for Hypertriglyceridemic Acute Pancreatitis: A Prospective RCT

Background: Hypertriglyceridemia-associated acute pancreatitis (HTG-AP) has become the second most common cause of acute pancreatitis in China, accounting for up to 42.4% of cases, with high recurrence rates and substantial disease burden. Disease severity and recurrence risk are potentially linked to triglyceride (TG) levels. Current lipid-lowering strategies have limitations in efficacy, onset speed, or safety. Increasing evidence suggests that gut microbiota dysbiosis and impaired intestinal barrier function contribute to lipid metabolism regulation and systemic inflammation in HTG-AP patients. Probiotic supplementation may offer a novel therapeutic approach by modulating gut microbiota, improving lipid metabolism, and alleviating inflammation.

Objective: To evaluate whether adjunctive treatment with Bacillus subtilis and Enterococcus faecium enteric-coated capsules (LCBE) reduces serum TG and inflammatory markers and improves clinical outcomes in mild to moderate HTG-AP patients.

Methods: This is a prospective, randomized, open-label, blinded endpoint (PROBE design), single-center, parallel-group clinical trial. A total of 180 eligible participants will be randomized 1:1 to the intervention group (standard therapy plus oral LCBE 500 mg three times daily for 28 days) or control group (standard therapy alone). The primary endpoints are serum TG, C-reactive protein (CRP), and interleukin-6 (IL-6) levels on day 5 post-intervention. Secondary endpoints include TG normalization rate (<1.7 mmol/L), lipid profile, inflammatory markers, glucose metabolism parameters, gut microbiota composition, intestinal barrier integrity, symptom relief, length of hospital stay, healthcare costs, quality of life, and safety.

Expected Impact: This study aims to provide high-level evidence for probiotic adjunctive therapy in HTG-AP and to explore underlying mechanisms from the perspective of gut microbiota modulation.

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Key information

Conditions

Hypertriglyceridemic Acute Pancreatitis Acute Pancreatitis, Hypertriglyceridemia-induced Digestive System Diseases Dyslipidemias Hyperlipidemia Hyperlipidemias Lipid Metabolism Disorders Metabolic Diseases Nutritional and Metabolic Diseases Pancreatic Diseases Pancreatitis

Age range

18 year–65 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 4

Primary location

About this study

Rationale:

Timely reduction of serum TG is critical for improving prognosis in HTG-AP. However, conventional therapies-including fibrates, insulin, heparin, and blood purification-have limitations related to onset speed, invasiveness, cost, and adverse effects. Preclinical and clinical studies suggest that Bacillus subtilisand Enterococcus faecium(LCBE) can improve lipid metabolism, restore gut microbial balance, enhance intestinal barrier function, and reduce systemic inflammation. Nevertheless, robust prospective RCT evidence focusing on TG dynamics in HTG-AP remains lacking.

Study Population and Setting:

Adult patients (18-65 years) diagnosed with mild HTG-AP (serum TG ≥11.3 mmol/L or 5.65-11.3 mmol/L with lactescent serum) within 72 hours of symptom onset will be enrolled from the Department of Gastroenterology, Zhongshan Hospital, Xiamen University. Patients with severe or moderately severe AP, other etiologies of AP, significant organ dysfunction, pregnancy, immunosuppression, diabetes mellitus, lactose intolerance, or recent use of antibiotics/probiotics will be excluded.

Intervention and Follow-up:

Participants will receive standard care according to the 2021 Chinese Expert Consensus on Emergency Management of HTG-AP, including fenofibrate, low-molecular-weight heparin, fluid resuscitation, somatostatin, ulinastatin, proton-pump inhibitors, nutritional support, and pain management. In addition, the intervention group will receive LCBE 500 mg (2 capsules) orally three times daily for 28 days. Follow-up visits are scheduled at baseline, day 5, day 14, and day 28, with serial assessments of TG, lipid profile, inflammatory cytokines, glucose metabolism, gut microbiota (16S rRNA sequencing), intestinal barrier biomarkers (D-lactate, endotoxin, DAO, zonulin), clinical symptoms, severity scores, and quality of life (EQ-5D-5L).

Statistical Analysis:

Analyses will follow the intention-to-treat principle, with per-protocol analysis as sensitivity analysis. Continuous variables will be compared using t-tests or Mann-Whitney U tests; categorical variables will be analyzed using chi-square or Fisher's exact tests. Microbiome diversity will be assessed using Shannon index, PERMANOVA, and LEfSe analysis. An independent Data Safety Monitoring Board will conduct one interim analysis when 50% enrollment is reached.

Ethical Considerations:

The study will be conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. Written informed consent will be obtained from all participants. The trial is approved by the Institutional Review Board of Zhongshan Hospital, Xiamen University

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Meet at least two of the three characteristic criteria for AP:① Acute onset of persistent upper abdominal pain;② Serum amylase and/or lipase activity at least three times above the upper limit of normal;③ Imaging findings on CT, MRI, or abdominal ultrasonography.
  • Meet the diagnostic criteria for hypertriglyceridemia-associated acute pancreatitis (HTG-AP): fulfill the AP diagnostic criteria and concurrent hypertriglyceridemia (serum triglycerides ≥11.3 mmol/L or 5.65-11.3 mmol/L with lactescent serum), with exclusion of other common causes of AP such as cholelithiasis and alcoholism.
  • Admission within 72 hours of symptom onset.
  • Disease severity assessed as mild acute pancreatitis (MAP) within 48 hours of admission, defined by absence of organ dysfunction and absence of local or systemic complications.
  • Age between 18 and 65 years.
  • No history of allergy to microbiological agents.
  • Signed informed consent obtained.

Exclusion criteria

  • Concurrent biliary, alcoholic, or other etiologies of acute pancreatitis;
  • Acute exacerbation of chronic pancreatitis or pancreatic tumor;
  • Severe hypertriglyceridemia-associated acute pancreatitis, defined as: ① patients classified as moderately severe or severe AP according to the Expert Consensus on the Diagnosis and Treatment of Hypertriglyceridemic Acute Pancreatitis; ② within 48 hours, meeting any one of the following criteria: modified Marshall score ≥2, MCTSI score ≥4, APACHE II score ≥15, BISAP score ≥3, or Ranson score ≥3; patients meeting any of these criteria are excluded;
  • Severe hepatic or renal dysfunction (serum creatinine >177 μmol/L or ALT >150 U/L);
  • Active infection, malignancy, immunodeficiency, or requiring long-term use of immunosuppressants;
  • Diagnosed diabetes mellitus;
  • Pregnancy or breastfeeding;
  • History of lactose intolerance;
  • Use within 4 weeks prior to enrollment of antibiotics, probiotics, prebiotics, synbiotics, or other microbiological agents, as well as gastrointestinal motility drugs (e.g., domperidone, mosapride) or other medications that may significantly affect gut microbiota or gastrointestinal function.

Treatment and study plan

Live Combined Bacillus subtilis and Enterococcus faecium Enteric-coated Capsules (LCBE)

Drug

LCBE 500 mg (2 capsules) orally three times daily for 28 ± 2 days, initiated within 24 hours after confirmation of eligibility.

Other names: Meichangan

Standard Care (in control arm)

Drug

Patients in the control group received standard care exclusively, in accordance with the 2021 Chinese Expert Consensus on the Emergency Diagnosis and Treatment of Hypertriglyceridemic Acute Pancreatitis. This regimen encompassed fenofibrate and low-molecular-weight heparin, alongside goal-directed fluid resuscitation. Comprehensive symptomatic and supportive therapies included somatostatin and ulinastatin infusions, proton pump inhibitor therapy, nutritional support, and analgesia management.

Primary outcomes

  1. Mean Concentration of Serum Triglycerides (TG) in mmol/L at 5 ± 2 days.

    Time frame: Baseline through Day 5 (±2 days)

    Blood samples will be collected after a minimum 8-hour fast. Serum triglycerides (TG) will be measured quantitatively using an enzymatic colorimetric assay on an automated clinical chemistry analyzer in the central laboratory of Xiamen University Zhongshan Hospital. The primary endpoint is the mean concentration of serum TG (in mmol/L) at the intervention visit occurring 5 ± 2 days after randomization. Values are presented as the mean (standard deviation, SD).

  2. Serum Concentration of C-Reactive Protein (CRP) at Day 5 (±2 days)

    Time frame: Baseline through Day 5 (±2 days)

    Fasting venous blood samples will be collected at the Day 5 (±2 days) visit. Serum CRP will be quantified using a high-sensitivity immunoturbidimetric assay, and will be presented as Mean (Standard Deviation) in mg/L.

  3. Serum Concentration of Interleukin-6 (IL-6) at Day 5 (±2 days)

    Time frame: Baseline through Day 5 (±2 days)

    Fasting venous blood samples will be collected at the Day 5 (±2 days) visit. Serum IL-6 will be measured via chemiluminescence immunoassay. Data will be presented as Mean (Standard Deviation) in pg/mL.

Secondary outcomes

  1. Mean Concentration of Serum Triglycerides (TG) in mmol/L at 14 ± 2 days

    Time frame: Baseline through Day 14 (±2 days)

    Blood samples will be collected after a minimum 8-hour fast. Serum triglycerides (TG) will be measured quantitatively using an enzymatic colorimetric assay on an automated clinical chemistry analyzer in the central laboratory of Xiamen University Zhongshan Hospital. The primary endpoint is the mean concentration of serum TG (in mmol/L) at the intervention visit occurring 14 ± 2 days after randomization. Values are presented as the mean (standard deviation, SD).

  2. Mean Concentration of Serum Triglycerides (TG) in mmol/L at 28 ± 2 days

    Time frame: Baseline through Day 28 (±2 days)

    Blood samples will be collected after a minimum 8-hour fast. Serum triglycerides (TG) will be measured quantitatively using an enzymatic colorimetric assay on an automated clinical chemistry analyzer in the central laboratory of Xiamen University Zhongshan Hospital. The primary endpoint is the mean concentration of serum TG (in mmol/L) at the intervention visit occurring 28 ± 2 days after randomization. Values are presented as the mean (standard deviation, SD).

  3. Serum Concentration of C-Reactive Protein (CRP) at Day 14 (±2 days)

    Time frame: Baseline through Day 14 (±2 days)

    Fasting venous blood samples will be collected at the Day 14 (±2 days) visit. Serum CRP will be quantified using a high-sensitivity immunoturbidimetric assay, and will be presented as Mean (Standard Deviation) in mg/L.

  4. Serum Concentration of C-Reactive Protein (CRP) at Day 28 (±2 days)

    Time frame: Baseline through Day 28 (±2 days)

    Fasting venous blood samples will be collected at the Day 28 (±2 days) visit. Serum CRP will be quantified using a high-sensitivity immunoturbidimetric assay, and will be presented as Mean (Standard Deviation) in mg/L.

  5. Percentage of Participants Achieving Serum Triglyceride (TG) Normalization (<1.7 mmol/L) at Day 5 (±2 days)

    Time frame: Baseline through Day 5 (±2 days)

    Serum TG levels will be measured from fasting blood samples collected at the Day 5 (±2 days) visit. Normalization is defined as a TG level <1.7 mmol/L. The outcome is the percentage of participants meeting this criterion at this specific timepoint.

  6. Percentage of Participants Achieving Serum Triglyceride (TG) Normalization (<1.7 mmol/L) at Day 14 (±2 days)

    Time frame: Baseline through Day 14 (±2 days)

    Serum TG levels will be measured from fasting blood samples collected at the Day 14 (±2 days) visit. Normalization is defined as a TG level <1.7 mmol/L. The outcome is the percentage of participants meeting this criterion at this specific timepoint.

  7. Percentage of Participants Achieving Serum Triglyceride (TG) Normalization (<1.7 mmol/L) at Day 28 (±2 days)

    Time frame: Baseline through Day 28 (±2 days)

    Serum TG levels will be measured from fasting blood samples collected at the Day 28 (±2 days) visit. Normalization is defined as a TG level <1.7 mmol/L. The outcome is the percentage of participants meeting this criterion at this specific timepoint.

  8. Percentage Change from Baseline in Serum Triglyceride (TG) Concentration at Day 5 (±2 days)

    Time frame: Baseline through Day 5 (±2 days)

    The percentage change will be calculated using the formula: [(TG at Day 5) - (TG at Baseline)] / (TG at Baseline) × 100%. Fasting blood samples will be collected at both timepoints. A negative value indicates a reduction in TG levels. Data will be presented as Mean (Standard Deviation, SD).

  9. Percentage Change from Baseline in Serum Triglyceride (TG) Concentration at Day 14 (±2 days)

    Time frame: Baseline through Day 14 (±2 days)

    The percentage change will be calculated using the formula: [(TG at Day 14) - (TG at Baseline)] / (TG at Baseline) × 100%. A negative value indicates a reduction in TG levels. Data will be presented as Mean (SD).

  10. Percentage Change from Baseline in Serum Triglyceride (TG) Concentration at Day 28 (±2 days)

    Time frame: Baseline through Day 28 (±2 days)

    The percentage change will be calculated using the formula: [(TG at Day 28) - (TG at Baseline)] / (TG at Baseline) × 100%. A negative value indicates a reduction in TG levels. Data will be presented as Mean (SD).

  11. Percentage Change from Baseline in Serum C-Reactive Protein (CRP) at Day 5 (±2 days)

    Time frame: Baseline through Day 5 (±2 days)

    The percentage change will be calculated as: [(CRP at Day 5) - (CRP at Baseline)] / (CRP at Baseline) × 100%. Serum CRP will be measured using a high-sensitivity immunoturbidimetric assay. A negative value indicates a reduction in systemic inflammation. Data will be presented as Median (Interquartile Range, IQR).

  12. Percentage Change from Baseline in Serum C-Reactive Protein (CRP) at Day 14 (±2 days)

    Time frame: Baseline through Day 14 (±2 days)

    The percentage change will be calculated as: [(CRP at Day 14) - (CRP at Baseline)] / (CRP at Baseline) × 100%. A negative value indicates a reduction in systemic inflammation. Data will be presented as Median (IQR).

  13. Percentage Change from Baseline in Serum C-Reactive Protein (CRP) at Day 28 (±2 days)

    Time frame: Baseline through Day 28 (±2 days)

    The percentage change will be calculated as: [(CRP at Day 28) - (CRP at Baseline)] / (CRP at Baseline) × 100%. A negative value indicates a reduction in systemic inflammation. Data will be presented as Median (IQR).

  14. Percentage Change from Baseline in Serum Interleukin-6 (IL-6) at Day 5 (±2 days)

    Time frame: Baseline through Day 5 (±2 days)

    The percentage change will be calculated as: [(IL-6 at Day 5) - (IL-6 at Baseline)] / (IL-6 at Baseline) × 100%. Serum IL-6 will be measured using a chemiluminescence immunoassay or ELISA. Data will be presented as Median (Interquartile Range, IQR).

  15. Change from Baseline in Gut Microbiota Alpha and Beta Diversity Indices Assessed by 16S rRNA Sequencing

    Time frame: Baseline through Day 28 (±2 days)

    Fecal samples will be collected at Baseline, Day 5, Day 14, and Day 28. Gut microbiota composition will be profiled using 16S rRNA gene sequencing (V3-V4 regions). Alpha diversity (including Shannon, Simpson, Chao1, and Observed OTUs indices) and beta diversity (using Bray-Curtis dissimilarity and Weighted UniFrac distances) will be calculated via the QIIME2 pipeline. Changes from baseline at each timepoint will be evaluated. LEfSe analysis will identify differentially abundant taxa (LDA score >2.0, P<0.05).

  16. Change from Baseline in Serum Intestinal Barrier Biomarkers (D-lactate, Endotoxin, DAO, Zonulin)

    Time frame: Baseline through Day 28 (±2 days)

    Fasting venous blood samples will be collected at Baseline, Day 5 (±2 days), Day 14 (±2 days), and Day 28 (±2 days). Serum will be separated and stored at -80°C until batch analysis. Biomarker concentrations will be measured using commercially available ELISA kits: D-lactate by enzymatic spectrophotometry, endotoxin by the chromogenic limulus amebocyte lysate (LAL) assay, diamine oxidase (DAO) by ELISA, and zonulin by ELISA. Changes from baseline at each timepoint will be calculated. Data will be presented as Mean (Standard Deviation, SD) or Median (Interquartile Range, IQR) as appropriate. These biomarkers will be correlated with gut microbiota profiles and clinical outcomes.

Other outcomes

  1. Time to Abdominal Pain Relief

    Time frame: From randomization up to Day 28 (±2 days)

    Abdominal pain intensity will be assessed every 2 hours by nursing staff using a Visual Analogue Scale (VAS; 0-100 mm) blinded to group allocation. Abdominal pain relief is defined as the time from randomization to the first instance when the VAS score decreases to ≤30 (mild pain or less) and remains at or below this level for at least 12 consecutive hours without rescue analgesia. Patients requiring surgical intervention, discharged, or experiencing a serious adverse event prior to achieving relief will be censored at the time of that event. Data will be presented as Median Time (Interquartile Range, IQR)

  2. Time to Successful Oral Feeding

    Time frame: From randomization up to Day 28 (±2 days)

    Defined as the time from randomization to the first instance when the participant tolerates a regular or semi-solid diet without experiencing recurrence of moderate to severe abdominal pain (Visual Analogue Scale, VAS >30) or other gastrointestinal symptoms (e.g., nausea, vomiting, abdominal distension) for at least 24 consecutive hours. Dietary tolerance will be assessed daily by the attending physician or study nurse blinded to group allocation. Patients requiring surgical intervention, discharged, or experiencing a serious adverse event prior to achieving successful oral feeding will be censored at the time of that event. Data will be presented as Median Time (Interquartile Range, IQR).

  3. Length of Hospital Stay

    Time frame: From admission to discharge, up to Day 28 (±2 days)

    Defined as the number of calendar days from the date of hospital admission to the date of discharge (discharge criteria: absence of abdominal pain, tolerance of solid food, and normalization of inflammatory markers). For participants transferred to another facility (e.g., ICU) or those who die during hospitalization, the length of stay will be censored at the date of the last known status. Data will be presented as Median (Interquartile Range, IQR) in days.

  4. Total Hospitalization Cost

    Time frame: From admission to discharge, up to Day 28 (±2 days)

    Total direct medical costs incurred from admission to discharge will be extracted from the hospital's electronic billing system. Costs include expenses related to medications (including study drugs), laboratory tests, imaging examinations, bed occupancy, surgical procedures, and medical consumables. All costs will be converted to Chinese Yuan (CNY) and adjusted for inflation if necessary. Costs for participants transferred to other facilities (e.g., ICU) or those who die during hospitalization will be calculated up to the date of the last known status. Data will be presented as Median (Interquartile Range, IQR) due to the typically skewed distribution of cost data.

  5. Rate of Intensive Care Unit (ICU) Admission During Hospitalization

    Time frame: From admission to discharge, up to Day 28 (±2 days)

    Defined as the proportion of participants who require transfer to or direct admission into an intensive care unit (ICU) at any point during the index hospitalization. This includes transfers for respiratory failure, hemodynamic instability, or organ support (e.g., mechanical ventilation, continuous renal replacement therapy). The outcome is assessed via daily review of medical records and nursing flow sheets. Data will be presented as a percentage with a 95% Confidence Interval (CI). Participants who die prior to a potential ICU transfer will be counted as having met the endpoint.

  6. Incidence of Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

    Time frame: From randomization to end of treatment (Day 28 ± 2 days)

    Adverse Events (AEs) and Serious Adverse Events (SAEs) will be monitored continuously from the time of informed consent until the end of the follow-up period (Day 28). AEs will be classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 6.0. The severity (Grade 1-5) and relationship to the study intervention (certain, probable/likely, possible, unlikely, unrelated) will be assessed by the investigator. SAEs will be reported to the Institutional Review Board and the sponsor within 24 hours. The incidence will be calculated as the number of participants experiencing at least one event divided by the total number of participants in each arm. Data will be presented as the number of participants (n) and percentage (%) with corresponding 95% Confidence Intervals.

  7. Quality of Life Assessed by EuroQol 5-Dimension 5-Level (EQ-5D-5L) Utility Score

    Time frame: Baseline through Day 28 (±2 days)

    Health-related quality of life (HRQoL) will be assessed using the EuroQol 5-Dimension 5-Level (EQ-5D-5L) questionnaire, a standardized generic instrument covering 5 domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Participants will complete the questionnaire independently at Baseline, Day 5 (±2 days), Day 14 (±2 days), and Day 28 (±2 days) under the guidance of study staff blinded to group allocation. Utility scores will be derived using the Chinese adult population preference-based scoring algorithm, with a theoretical range of -0.391 (worst possible health state, equivalent to coma/death) to 1.0 (full health). Higher scores indicate better HRQoL; lower scores reflect greater impairment in daily functioning and well-being. Data will be presented as Mean (Standard Deviation, SD), with sensitivity analyses using Median (Interquartile Range, IQR) if data deviate from normality.

Study contacts

Contact information is provided by the study sponsor or research team.

Liu Yunpeng PhD

CONTACT

[email protected]

86-0592-2292232

Xu Hongzhi PhD

CONTACT

[email protected]

86-0592-2292232

Sponsors and collaborators

Lead sponsor

Jianyin Zhou

Other

Registry information

Official study title

Effect of Bacillus Subtilis and Enterococcus Faecium Combination Therapy Combined With Conventional Lipid-Lowering Treatment on Triglyceride Levels in Patients With Hypertriglyceridemic Acute Pancreatitis: A Prospective Randomized Controlled Trial

Important dates

Study start
2026
Primary completion
2028
Study completion
2029
First posted
Jul 22, 2026
Registry last updated
Jul 22, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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