Fuzheng Huayu Tablets for Metabolic Dysfunction-Associated Fatty Liver Cirrhosis (Compensated): A Randomized, Double-Blind, Placebo-Controlled, Multicenter Clinical Study

This study aims to enroll 459 eligible patients aged 18-75 years with compensated metabolic dysfunction-associated fatty liver cirrhosis. Patients will be randomized to the treatment group (Fuzheng Huayu Tablets, 4 tablets three times daily) or the control group (matching placebo, 4 tablets three times daily) for 72 weeks. The primary efficacy endpoint is the proportion of patients with ≥10% reduction in liver stiffness measurement (LSM) at Week 24 compared to baseline. Secondary endpoints include changes in liver function, fibrosis markers, Child-Pugh score, and adverse event incidence. All safety assessments will be performed throughout the study.

Inclusion criteria

• Aged 18 to 75 years (inclusive of both upper and lower limits).
• Diagnosed with compensated metabolic dysfunction-associated fatty liver cirrhosis, meeting all three of the following conditions:

(1) At screening, FibroScan liver stiffness measurement (LSM) ≥ 20 kPa, OR LSM ≥ 15 kPa AND any one of the following: platelet count < 150×10⁹/L, or FIB-4 ≥ 3.48, or Agile4 ≥ 0.57; (2) Has a history of metabolic dysfunction or metabolic dysfunction-associated fatty liver disease (MAFLD); (3) Child-Turcotte-Pugh score < 7 and MELD score < 12. 3. Voluntarily participates in the clinical study and agrees to sign the informed consent form.

Exclusion criteria

• History or current hepatic decompensation events at screening, including but not limited to the following: a) Esophagogastric variceal bleeding; b) Hepatic ascites requiring diuretic treatment; c) Hepatic encephalopathy (West Haven grade 2 or above); d) Hepatorenal syndrome.
• Having a history or evidence of other chronic liver diseases, such as alcoholic liver disease, drug-induced liver disease, primary biliary cholangitis, primary sclerosing cholangitis, autoimmune hepatitis or overlap syndrome, Wilson's disease, alpha-1 antitrypsin deficiency, hereditary hemochromatosis, history of biliary obstruction or biliary shunt, metastatic liver cancer; Hepatitis B (HBsAg positive); Hepatitis C (HCV antibody positive and HCV-RNA positive). Subjects with previous hepatitis C treatment must maintain negative HCV-RNA results for at least 3 years before screening to be eligible.
• History of liver transplantation, on the liver transplantation waiting list, or history of TIPS operation.
• Use of anti-obesity drugs within 3 months prior to screening and during the whole trial is prohibited, including bupropion-naltrexone, orlistat, phentermine, phentermine/topiramate and anti-obesity supplements. Subjects planning to receive metabolic bariatric surgery during the study will be excluded (excluding acupuncture weight loss, liposuction or abdominal lipectomy performed more than 1 year before screening).
• Type 1 diabetes mellitus; uncontrolled type 2 diabetes mellitus, defined as HbA1c > 9% at screening or within 60 days before randomization. Subjects with HbA1c > 9% may be re-screened once no less than 3 months after the initial screening failure; insulin dosage adjustment more than 20% within 60 days before randomization is also excluded.
• Unstable use of drugs that may affect efficacy evaluation within 3 months prior to screening, including but not limited to Vitamin E (dose > 400 IU/d), thiazolidinediones (TZDs), SGLT-2 inhibitors, GLP-1 receptor agonists, and chiglitazar. Those who have taken stable dosage continuously until screening visit and will maintain relatively stable dosage throughout the study period are allowed to enroll.
• Use of drugs that may induce hepatic steatosis or steatohepatitis for at least 4 weeks within 6 months prior to screening (e.g., valproic acid, tamoxifen, methotrexate, amiodarone, long-term oral corticosteroids > 5 mg/d prednisone equivalent, or estrogen at doses higher than contraception or hormone replacement therapy). The above drugs are prohibited throughout the trial until the end of follow-up. Subjects requiring bronchodilators, topical, inhaled, nasal corticosteroids or caudal steroid injections are not excluded.
• Use of Chinese herbal medicine and proprietary Chinese medicines with anti-fibrotic or MAFLD therapeutic effects within 3 months prior to screening, including but not limited to Compound Biejia Ruangan Capsules, Anluo Huaxian Pills, Qianggan Capsules/Tablets. If the medication course is no more than 3 months, subjects can be enrolled after a 1-month washout period.
• Uncontrolled hypertension at screening, defined as systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg.
• Occurrence of myocardial infarction, unstable angina, malignant arrhythmia, percutaneous coronary intervention, coronary artery bypass grafting, ischemic or hemorrhagic stroke, transient ischemic attack, acute peripheral vascular events within 6 months prior to screening.
• Active severe diseases or malignant tumors with a life expectancy of less than 5 years.
• Uncontrolled hypothyroidism or hyperthyroidism at screening (assessed by the investigator). Participants with hypothyroidism receiving stable-dose thyroid hormone replacement therapy for at least 2 months before screening can be enrolled.
• Abnormal laboratory indicators at screening: ALT > 5 × ULN, AST > 5 × ULN, ALP ≥ 2 × ULN (unless ALP elevation is non-hepatic origin), eGFR < 45 mL/min/1.73m², INR > 1.5 × ULN, total bilirubin > 1.5 × ULN (for participants with Gilbert syndrome, TBIL threshold ≥ 3 × ULN), ALB < 28 g/L.
• Thrombocytopenia caused by hematological diseases such as immune thrombocytopenic purpura, drug influence or active infection.
• Female subjects who are pregnant, breastfeeding or planning to become pregnant during the trial.
• Allergy to the investigational drug or its ingredients.
• Subjects who are expected to be unable to comply with the study protocol or fail to complete the trial as planned.