Metabolic-associated Fatty Liver Disease
Conditions
Keywords
metabolic-associated fatty liver disease, Rifaximin
Brief summary
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).
Interventions
Participants will receive oral rifaximin at a dosage of 1200 mg/day (400 mg, three times daily) for 24 weeks.
Sponsors
Shanghai Changzheng Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Participants will receive oral rifaximin at a dosage of 1200 mg/day (400 mg, three times daily) for 24 weeks.
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Willing and able to provide written informed consent; 2. Aged 18 to 75 years, regardless of gender; 3. Diagnosed with fatty liver disease within the past 6 months; 4. Presence of at least one of the following metabolic abnormalities: (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
1. Cirrhosis - Confirmed by clinical, laboratory, imaging, and/or liver biopsy. 2. Chronic liver disease of other etiologies (e.g., viral/autoimmune hepatitis, alcoholic liver disease, drug-induced liver injury) 3. Secondary hepatic steatosis (e.g., drug-induced, total parenteral nutrition-related, or hypothyroidism-associated); 4. Recent use of intestinal flora-modifying agents, or unstable regimens of medications (including hepatoprotectants, metformin, thiazolidinediones, fibrates, statins, et al) within 4 weeks prior to enrollment; 5. Agents with potential effects on MAFLD progression administered within 12 weeks prior to enrollment, excluding those maintained at stable doses for ≥24 weeks (e.g., Glucagon-like peptide-1 receptor agonists, Dipeptidyl peptidase IV inhibitors, Obeticholic acid, Sodium-glucose cotransporter 2 inhibitors, Resmetirom or anti-obesity medications) 6. Poorly controlled diabetes (HbA1c \>9%) 7. Jaundice (total bilirubin ≥85 μmol/L), or Renal dysfunction (serum creatinine ≥1.2 × ULN) 8. History of bariatric surgery 9. Active or suspected malignancy 10. Severe systemic conditions - Including: Inflammatory diseases (e.g., connective tissue disorders), Biliary/pancreatic disorders, Chronic/acute infections, Severe cardiovascular, pulmonary, or hematologic diseases, Myocardial infarction or stroke within 6 months, Psychiatric disorders 11. HIV infection 12. Known hypersensitivity to rifaximin 13. MRI contraindications - Including: Metal implants, Claustrophobia, Body size exceeding scanner capacity 14. Pregnancy, lactation, or planned pregnancy 15. Participation in another drug trial within 3 months 16. Other conditions deemed unsuitable by investigators
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The change in liver fat content measured by MRI at 24 weeks of treatment. | From enrollment to the end of treatment at 24 weeks | Absolute and relative changes in MRI-measured liver proton density fat fraction (PDFF) at 24 weeks compared to baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Proportion of patients achieving ≥30% reduction in liver fat content measured by MRI-PDFF at 24 weeks of treatment compared to baseline |
| The change in liver fat content measured by MRI-PDFF at 12 weeks of treatment. | From enrollment to the end of treatment at 24 weeks | Absolute and relative changes in MRI-measured liver PDFF at 12 weeks compared to baseline. |
| Proportion of patients achieving ≥30% reduction in liver fat content (PDFF) measured by MRI at 12 weeks of treatment compared to baseline. | From enrollment to the end of treatment at 24 weeks | The proportion of patients whose liver fat content (PDFF), assessed via MRI, decreased by ≥30% from baseline after 12 weeks of treatment. |
| Changes in liver function indicators after 12 weeks of treatment compared to baseline. | From enrollment to the end of treatment at 12 weeks | Changes in liver function parameters from baseline after 12 weeks of treatment. |
| Changes in liver function indicators after 24 weeks of treatment compared to baseline. | From enrollment to the end of treatment at 24 weeks | Changes in liver function indicators after 24 weeks of treatment compared to baseline. |
| Change in liver fat content assessed via FibroScan after 12 weeks of treatment compared to baseline. | From enrollment to the end of treatment at 12 weeks | Change in controlled attenuation parameter (CAP) values, measured by FibroScan, from baseline after 12 weeks of therapy |
| Change in liver fat content assessed via FibroScan after 24 weeks of treatment compared to baseline. | From enrollment to the end of treatment at 24 weeks | Change in controlled attenuation parameter (CAP) values, measured by FibroScan, from baseline after 24 weeks of therapy |
| Changes in fatty liver index (FLI) after 12 and 24 weeks of treatment compared to baseline. | From enrollment to the end of treatment at 12 and 24 weeks | 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. |
| Changes in NAFLD-liver fatty score（NAFLD-LFS）after 12 and 24 weeks of treatment compared to baseline. | From enrollment to the end of treatment at 12 and 24 weeks | 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. |
| Changes in AST-to-Platelet Ratio Index (APRI) after 12 and 24 weeks of treatment compared to baseline. | From enrollment to the end of treatment at 12 and 24 weeks | 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. |
| Changes in Fibrosis 4 (FIB-4) Score after 12 and 24 weeks of treatment | From enrollment to the end of treatment at 12 and 24 weeks | 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. |
| Changes in FibroScan-AST (FAST) Score after 12 and 24 weeks of treatment compared to baseline. | From enrollment to the end of treatment at 12 and 24 weeks | 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. |
| Changes in Body Mass Index (BMI) at 12 and 24 weeks of treatment compared to baseline. | From enrollment to the end of treatment at 12 and 24 weeks | BMI calculation Formula: BMI = Weight (kilograms) ÷ \[Height (meters)\]² |
| Changes in Waist circumference (WC) at 12 and 24 weeks of treatment compared to baseline. | From enrollment to the end of treatment at 12 and 24 weeks | Waist circumference (WC) is measured 3 cm above the navel. |
| Changes in visceral adipose tissue (VAT) at 12 and 24 weeks of treatment compared to baseline. | From enrollment to the end of treatment at 12 and 24 weeks | 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). |
| Changes in abdominal subcutaneous adipose tissue (ASAT) from baseline after 12 and 24 weeks of therapy. | From enrollment to the end of treatment at 12 and 24 weeks | 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). |
| Changes in Cholesterol from baseline after 12 and 24 weeks of therapy. | From enrollment to the end of treatment at 12 and 24 weeks | Cholesterol testing should be performed in the morning after an overnight fast. |
| Changes in triglyceride from baseline after 12 and 24 weeks of therapy. | From enrollment to the end of treatment at 12 and 24 weeks | Triglyceride testing should be performed in the morning after an overnight fast. |
| Changes in Hemoglobin A1c (HbA1c) from baseline after 12 and 24 weeks of therapy. | From enrollment to the end of treatment at 12 and 24 weeks | Change from baseline in HbA1c absolute concentration (mmol/mol) and percentage of total hemoglobin (%) after 12 and 24 weeks of therapy. |
| Changes in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) from baseline after 12 and 24 weeks of therapy. | From enrollment to the end of treatment at 12 and 24 weeks | 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. |
| The frequency and severity of treatment-related adverse events (AEs) as assessed by CTCAE 5.0. | From enrollment to the end of treatment at 24 weeks | The safety assessment involved monitoring changes in symptoms, vital signs, and laboratory parameters during treatment. |
| Changes in NAFLD fibrosis score (NFS) after 12 and 24 weeks of treatment compared to baseline. | From enrollment to the end of treatment at 12 and 24 weeks | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Changes in liver fat content assessed via MRI-PDFF during extended treatment (36 or 48 weeks) and at 12/24 weeks post-treatment. | Through study completion, an average of 3 years | 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 |
Countries
China
Contacts
Primary ContactCHUAN YIN, M.D.
Outcome results
None listed