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Study Objective: to evaluate the efficacy and safety of rifaximin in the treatment of metabolic-associated fatty liver disease (MAFLD), and investigate the underlying mechanisms by which rifaximin influence MAFLD progression.
Target Population: patients diagnosed with MAFLD. Intervention: this single-center, single-arm exploratory study will enroll up to 40 eligible MAFLD patients who meet the inclusion criteria, do not meet any exclusion criteria, and provide written informed consent. Participants will receive oral rifaximin at a dosage of 1200 mg/day (400 mg, three times daily) for 24 weeks. Patients will be advised to maintain their usual physical activity and adhere to a recommended dietary plan (e.g., Mediterranean diet). Concurrent therapies such as hepatoprotective agents, lipid-lowering medications, and antihypertensive treatments will remain unchanged, with close monitoring of relevant parameters. No additional prescription or over-the-counter drugs that may affect fatty liver progression or alter gut microbiota composition will be permitted during the study.
The primary endpoint will be assessed at 24 weeks. If liver proton density fat fraction (PDFF) remains ≥ 8% after 24 weeks of rifaximin therapy, treatment will be extended for an additional 12 weeks, followed by reevaluation of PDFF changes. The maximum total treatment duration will not exceed 48 weeks. All patients will undergo a 24-week post-treatment follow-up period after discontinuation of rifaximin.
Investigational Drug: Rifaximin (Alfa Wassermann S.p.A., Italy).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Rifaximin treatment group | Experimental | Participants will receive oral rifaximin. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Rifaximin (Xifaxan) | Drug | Participants will receive oral rifaximin at a dosage of 1200 mg/day (400 mg, three times daily) for 24 weeks. |
|
| Measure | Description | Time Frame |
|---|---|---|
| The change in liver fat content measured by MRI at 24 weeks of treatment. | Absolute and relative changes in MRI-measured liver proton density fat fraction (PDFF) at 24 weeks compared to baseline. | From enrollment to the end of treatment at 24 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Proportion of patients achieving ≥30% reduction in liver fat content measured by MRI-PDFF at 24 weeks of treatment compared to baseline | Proportion of patients achieving ≥30% reduction in liver fat content measured by MRI-PDFF at 24 weeks of treatment compared to baseline | From enrollment to the end of treatment at 24 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Changes in liver fat content assessed via MRI-PDFF during extended treatment (36 or 48 weeks) and at 12/24 weeks post-treatment. | Longitudinal changes in liver PDFF measured by MRI during extended therapy (36 or 48 weeks) and after treatment discontinuation (12 and 24 weeks post-treatment), compared to baseline values | Through study completion, an average of 3 years |
Inclusion Criteria:
(1) Overweight or obesity (BMI ≥23 kg/m²) (2) Type 2 diabetes (T2DM) (3) Clinical evidence of metabolic dysfunction (defined as meeting at least two of the following criteria): A. Waist circumference ≥90 cm for males or ≥80 cm for females B. Blood pressure ≥130/85 mmHg and/or diagnosed hypertension under treatment C. Fasting plasma triglycerides ≥1.7 mmol/L (150 mg/dL) or diagnosed hypertriglyceridemia under treatment D. Fasting HDL-C <1.0 mmol/L (40 mg/dL) for males or <1.3 mmol/L (50 mg/dL) for females, or diagnosed dyslipidemia under treatment E. Prediabetes: fasting glucose 5.6-6.9 mmol/L (100-125 mg/dL) or 2-hour postprandial glucose 7.8-11.0 mmol/L (140-199 mg/dL) or HbA1c 5.7%-6.4% (39-47 mmol/mol) F. Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) score ≥2.5 G. Plasma high-sensitivity C-reactive protein (hs-CRP) >2 mg/L 5. Liver fat content ≥8% as measured by MRI proton density fat fraction (MRI-PDFF).
Exclusion Criteria
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| CHUAN YIN, M.D. | Contact | +8613482705212 | ilse1225@163.com |
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Changzheng Hospital, Naval Medical University, shanghai, China | Recruiting | Shanghai | Shanghai Municipality | 200003 | China |
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| ID | Term |
|---|---|
| D000078262 | Rifaximin |
| ID | Term |
|---|---|
| D012294 | Rifamycins |
| D006576 | Heterocyclic Compounds, 4 or More Rings |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
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Participants will receive oral rifaximin at a dosage of 1200 mg/day (400 mg, three times daily) for 24 weeks.
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| The change in liver fat content measured by MRI-PDFF at 12 weeks of treatment. |
Absolute and relative changes in MRI-measured liver PDFF at 12 weeks compared to baseline. |
| From enrollment to the end of treatment at 24 weeks |
| Proportion of patients achieving ≥30% reduction in liver fat content (PDFF) measured by MRI at 12 weeks of treatment compared to baseline. | The proportion of patients whose liver fat content (PDFF), assessed via MRI, decreased by ≥30% from baseline after 12 weeks of treatment. | From enrollment to the end of treatment at 24 weeks |
| Changes in liver function indicators after 12 weeks of treatment compared to baseline. | Changes in liver function parameters from baseline after 12 weeks of treatment. | From enrollment to the end of treatment at 12 weeks |
| Changes in liver function indicators after 24 weeks of treatment compared to baseline. | Changes in liver function indicators after 24 weeks of treatment compared to baseline. | From enrollment to the end of treatment at 24 weeks |
| Change in liver fat content assessed via FibroScan after 12 weeks of treatment compared to baseline. | Change in controlled attenuation parameter (CAP) values, measured by FibroScan, from baseline after 12 weeks of therapy | From enrollment to the end of treatment at 12 weeks |
| Change in liver fat content assessed via FibroScan after 24 weeks of treatment compared to baseline. | Change in controlled attenuation parameter (CAP) values, measured by FibroScan, from baseline after 24 weeks of therapy | From enrollment to the end of treatment at 24 weeks |
| Changes in fatty liver index (FLI) after 12 and 24 weeks of treatment compared to baseline. | FLI is utilized to assess the severity of hepatic steatosis. Its calculation formula is based on laboratory and anthropometric measurements, including triglyceride (TG) and gamma-glutamyl transferase (GGT) levels, body mass index (BMI), and waist circumference (WC). FLI = (e^(0.953 * ln(triglycerides) + 0.139 * BMI + 0.718 * ln(ggt) + 0.053 * waist circumference - 15.745)) / (1 + e^(0.953 * ln(triglycerides) + 0.139 * BMI + 0.718 * ln(ggt) + 0.053 * waist circumference - 15.745)) * 100 A FLI value below 30 can be used to rule out steatosis (sensitivity = 87%; negative likelihood ratio [LR-] = 0.2), while a FLI value equal to or above 60 can be used to rule in hepatic steatosis. | From enrollment to the end of treatment at 12 and 24 weeks |
| Changes in NAFLD-liver fatty score（NAFLD-LFS）after 12 and 24 weeks of treatment compared to baseline. | NAFLD-LFS Calculation Formula: NAFLD-LFS = -2.89 + 0.45 × Type 2 Diabetes (yes=2, no=0) + 1.18 × Metabolic Syndrome (yes=1, no=0) + 0.15 × Insulin (mU/L) + 0.04 × AST (U/L) - 0.94 × (AST/ALT Ratio). Interpretation of Scores: NAFLD-LFS < -1.0: Suggests low liver fat content and a low likelihood of significant steatosis. -1.0 ≤ NAFLD-LFS ≤ 0.5: Intermediate range; further evaluation with additional tests (e.g., imaging or biopsy) is recommended. NAFLD-LFS > 0.5: Indicates high liver fat content and the presence of significant steatosis, requiring clinical intervention. | From enrollment to the end of treatment at 12 and 24 weeks |
| Changes in AST-to-Platelet Ratio Index (APRI) after 12 and 24 weeks of treatment compared to baseline. | APRI is calculated using the following formula: APRI = [ (AST Level (U/L) / AST ULN (Upper Limit of Normal)) / Platelet Count (10⁹/L) ] × 100 Interpretation: APRI < 0.5: Suggests the absence of significant fibrosis (high negative predictive value). APRI > 2.0: Highly indicative of cirrhosis (high positive predictive value). Intermediate values (0.5 ≤ APRI ≤ 2.0): Further evaluation with additional tests-such as liver elastography, FIB-4 index, or liver biopsy-is recommended for accurate assessment. | From enrollment to the end of treatment at 12 and 24 weeks |
| Changes in Fibrosis 4 (FIB-4) Score after 12 and 24 weeks of treatment | The FIB-4 index is primarily used to stratify the risk of liver fibrosis and is calculated using the following formula: FIB-4= Age (years) × AST (U/L)/ [Platelet Count (10⁹/L)×√ALT(U/L)]. The criteria are categorized as follows: Low Risk (FIB-4 < 1.3) suggests minimal or no fibrosis (F0-F1). Liver biopsy or elastography may be deferred in such cases. Intermediate Risk (1.3 ≤ FIB-4 ≤ 2.67): Further evaluation with additional tests-such as liver elastography, APRI, or liver biopsy-is recommended. Significant fibrosis (F2-F3) may be present, warranting closer monitoring. High Risk (FIB-4 > 2.67): Highly suggestive of advanced fibrosis or cirrhosis (F3-F4). Confirmatory tests like elastography or liver biopsy should be prioritized. This range has a high positive predictive value. | From enrollment to the end of treatment at 12 and 24 weeks |
| Changes in NAFLD fibrosis score (NFS) after 12 and 24 weeks of treatment compared to baseline. | NFS calculation formula: NFS= [-1.675+0.037×Age (years)+0.094×BMI（kg/m2+1.13×IFG/Diabetes (yes = 1, no = 0) +0.99）× (AST/ALT Ratio) +0.013×PLT(×109/L)-0.66×ALB（g/dl）] Interpretation Guidelines: NFS < -1.455: Low probability of significant fibrosis (F2-F4). NFS > 0.676: High probability of advanced fibrosis (F3-F4). NFS between -1.455 and 0.676: Indeterminate range; further evaluation with additional tests (e.g., elastography or liver biopsy) is recommended. | From enrollment to the end of treatment at 12 and 24 weeks |
| Changes in FibroScan-AST (FAST) Score after 12 and 24 weeks of treatment compared to baseline. | The FAST Score is a non-invasive composite index used to assess the likelihood of both significant fibrosis (≥F2) and active steatohepatitis (NASH) in patients withMASLD. It integrates Liver Stiffness Measurement (LSM) obtained via FibroScan® and the serum biomarker AST. FAST Score Calculation Formula: FAST = e^(-1.65 + 1.07 × ln(LSM) + 2.66 × 10^(-8) × AST^3 - 63.3 × AST^(-1) - 0.009 × PLT) / (1 + e^(-1.65 + 1.07 × ln(LSM) + 2.66 × 10^(-8) × AST^3 - 63.3 × AST^(-1) - 0.009 × PLT)). Interpretation Guidelines: FAST < 0.35: Low probability of significant fibrosis (≥F2) with active inflammation (NASH). Negative predictive value >90%. Liver biopsy may be avoided. FAST > 0.67: High probability of both significant fibrosis (≥F2) and active inflammation (NASH). Positive predictive value >70%. Further evaluation or intervention is recommended. FAST between 0.35-0.67: Gray zone; comprehensive assessment with additional methods. | From enrollment to the end of treatment at 12 and 24 weeks |
| Changes in Body Mass Index (BMI) at 12 and 24 weeks of treatment compared to baseline. | BMI calculation Formula: BMI = Weight (kilograms) ÷ [Height (meters)]² | From enrollment to the end of treatment at 12 and 24 weeks |
| Changes in Waist circumference (WC) at 12 and 24 weeks of treatment compared to baseline. | Waist circumference (WC) is measured 3 cm above the navel. | From enrollment to the end of treatment at 12 and 24 weeks |
| Changes in visceral adipose tissue (VAT) at 12 and 24 weeks of treatment compared to baseline. | VAT was quantified using 3D Slicer software by manually segmenting regions of interest (ROIs) within the intra-abdominal cavity on MRI images at the level of the third lumbar vertebra (L3). | From enrollment to the end of treatment at 12 and 24 weeks |
| Changes in abdominal subcutaneous adipose tissue (ASAT) from baseline after 12 and 24 weeks of therapy. | ASAT volume was quantified using 3D Slicer software by manually segmenting regions of interest (ROIs) within the subcutaneous fat compartment on MRI images at the level of the third lumbar vertebra (L3). | From enrollment to the end of treatment at 12 and 24 weeks |
| Changes in Cholesterol from baseline after 12 and 24 weeks of therapy. | Cholesterol testing should be performed in the morning after an overnight fast. | From enrollment to the end of treatment at 12 and 24 weeks |
| Changes in triglyceride from baseline after 12 and 24 weeks of therapy. | Triglyceride testing should be performed in the morning after an overnight fast. | From enrollment to the end of treatment at 12 and 24 weeks |
| Changes in Hemoglobin A1c (HbA1c) from baseline after 12 and 24 weeks of therapy. | Change from baseline in HbA1c absolute concentration (mmol/mol) and percentage of total hemoglobin (%) after 12 and 24 weeks of therapy. | From enrollment to the end of treatment at 12 and 24 weeks |
| Changes in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) from baseline after 12 and 24 weeks of therapy. | HOMA-IR Calculation Formula: HOMA-IR = [Fasting Insulin (μIU/mL) × Fasting Glucose (mmol/L)] / 22.5. Increase in HOMA-IR suggests worsening insulin resistance. Decrease in HOMA-IR indicates improved insulin sensitivity. | From enrollment to the end of treatment at 12 and 24 weeks |
| The frequency and severity of treatment-related adverse events (AEs) as assessed by CTCAE 5.0. | The safety assessment involved monitoring changes in symptoms, vital signs, and laboratory parameters during treatment. | From enrollment to the end of treatment at 24 weeks |
| D047029 | Lactams, Macrocyclic |
| D047028 | Macrocyclic Compounds |
| D011083 | Polycyclic Compounds |