Phase I/II Trial of Human Umbilical Cord Mesenchymal Stromal Cells for UDCA-Refractory Primary Biliary Cholangitis

This is a phase I/II clinical trial. The phase I component uses a conventional "3+3" dose-escalation design with three dose levels: low (1.0×10⁸ cells), medium (1.5×10⁸ cells), and high (2.0×10⁸ cells). Each dose cohort enrolls 3-6 evaluable participants, for a total of 18-36 evaluable subjects. Phase Ia is a single-dose stage, with dose-limiting toxicity (DLT) assessed up to 7 days after the infusion. Phase Ib is a multiple-dose stage, in which participants receive one intravenous infusion weekly for 3 consecutive weeks, and DLT is evaluated up to 28 days after the first dose. The aim is to determine the maximum tolerated dose (MTD) and/or the recommended phase II dose (RP2D).

The phase II component plans to enroll 50 patients with primary biliary cholangitis, who will be randomized in a 2:2:1 ratio to receive either dose level 1 (1.5×10⁸ cells), dose level 2 (2.0×10⁸ cells), or placebo control, with the final dose to be confirmed based on the results of phase I. The treatment regimen consists of one intravenous infusion weekly for 3 consecutive weeks. The primary objective of phase II is to evaluate preliminary efficacy.

Inclusion criteria

• Voluntary participation and signed informed consent.
• Age 18 to 75 years, both genders.
• Diagnosis of PBC per the 2025 PBC Guideline of the National Health Commission of China, meeting at least 2 of the following 3 criteria:

• Biochemical evidence of cholestasis (predominantly elevated ALP and GGT) with imaging excluding extrahepatic or intrahepatic large bile duct obstruction;
• Positive for anti-mitochondrial antibody (AMA)/AMA-M2, or other PBC-specific autoantibodies (anti-gp210, anti-sp100);
• Histological evidence of non-suppurative destructive cholangitis and small bile duct destruction.
• Inadequate response to UDCA prior to enrollment, defined as ALP ≥1.67×ULN after at least 6 months of UDCA therapy (with stable dose for ≥3 months before screening).
• 1.67×ULN ≤ ALP < 10×ULN and total bilirubin ≤ 3×ULN at screening.
• If taking colchicine, stable dose for ≥3 months before screening.
• If taking medications for pruritus (e.g., cholestyramine, rifampicin, naltrexone, sertraline), stable dose for ≥3 months before screening.
• If taking statins or ezetimibe, stable dose for ≥2 months before screening.

Exclusion criteria

• Concurrent or previous other liver diseases, including but not limited to: chronic hepatitis B, chronic hepatitis C, primary sclerosing cholangitis (PSC), complete biliary obstruction, alcoholic liver disease, autoimmune hepatitis or overlap with other autoimmune liver diseases, non-alcoholic steatohepatitis (NASH), suspected or confirmed Gilbert's syndrome.
• Decompensated cirrhosis (defined as presence of at least one of: esophageal/gastric variceal bleeding, hepatic encephalopathy, ascites, hepatorenal syndrome) based on clinical, laboratory, imaging, or histopathological findings.
• Any of the following laboratory abnormalities at screening: creatinine ≥1.5×ULN or creatinine clearance <60 mL/min; ALT and/or AST >5×ULN; albumin <30 g/L; creatine kinase >2×ULN; platelet count < lower limit of normal; INR ≥1.5 or prothrombin activity ≤40%.
• Diseases that may cause non-hepatic elevation of alkaline phosphatase (e.g., Paget's disease).
• Use of prohibited medications within specified washout periods:

• Within 2 months before screening: fibrates and glitazones;
• Within 3 months before screening: obeticholic acid, azathioprine, cyclosporine, methotrexate, mycophenolate mofetil, pentoxifylline, budesonide and other systemic corticosteroids by long-term parenteral or oral administration only, and hepatotoxic drugs (e.g., α-methyldopa, valproate, isoniazid, nitrofurantoin);
• Within 12 months before screening: antibodies or immunotherapies targeting interleukins or other cytokines/chemokines.
• Uncontrolled cardiovascular, digestive, respiratory, urinary, neurological, psychiatric disorders (including substance/alcohol abuse), immunodeficiency, or severe autoimmune diseases, or any condition that may limit life expectancy to <2 years, or judged by the investigator as unsuitable for participation.
• History of malignancy within the past 2 years (except localized squamous cell carcinoma of skin or treated cervical intraepithelial neoplasia), regardless of treatment or evidence of local recurrence/metastasis.
• Received any other investigational drug or participated in another interventional clinical trial within 3 months before screening; prior use of elafibranor or seladelpar.
• History of drug or alcohol abuse within 1 year before screening.
• Pregnant, planning pregnancy, or women of childbearing potential unwilling to use effective contraception (≥1 method) during the study and for 30 days after last dose; breastfeeding women.
• Co-infection with HIV or syphilis.
• Known allergy to any component of the study drug.
• Psychologically unstable or incapacitated, unable to provide valid informed consent or comply with study procedures.
• Any other condition judged by the investigator as unsuitable for enrollment, or that may interfere with the analysis of study results.