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.
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.
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);
Parallel
Live Combined Bacillus subtilis and Enterococcus faecium Enteric-coated Capsules (LCBE)
DrugLCBE 500 mg (2 capsules) orally three times daily for 28 ± 2 days, initiated within 24 hours after confirmation of eligibility.
Standard Care (in control arm)
DrugPatients 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.
Mean Concentration of Serum Triglycerides (TG) in mmol/L at 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).
Serum Concentration of C-Reactive Protein (CRP) at 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.
Serum Concentration of Interleukin-6 (IL-6) at 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.
Mean Concentration of Serum Triglycerides (TG) in mmol/L at 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).
Mean Concentration of Serum Triglycerides (TG) in mmol/L at 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).
Serum Concentration of C-Reactive Protein (CRP) at 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.
Serum Concentration of C-Reactive Protein (CRP) at 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.
Time to Abdominal Pain Relief
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)
Time to Successful Oral Feeding
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).
Length of Hospital Stay
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.
Total Hospitalization Cost
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.
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Jianyin Zhou
Lead sponsor
Zhongshan Hospital Xiamen University
Sponsor institution
