This phase I/II clinical trial evaluates human umbilical cord-derived mesenchymal stromal cell (hUC-MSC) injection in patients with primary biliary cholangitis (PBC). The phase I component uses a 3+3 dose-escalation design with separate single-dose and multiple-dose stages to assess safety and tolerability, establish the maximum tolerated dose and recommended phase II dose, while monitoring adverse events, vital signs, laboratory parameters, and immunogenicity, and to explore preliminary efficacy signals. The phase II component is a randomized, double-blind, placebo-controlled trial with the primary endpoint of composite response of alkaline phosphatase and bilirubin at 12 weeks to evaluate efficacy, alongside continuous safety surveillance. Systematic measurements of liver function, cholestasis, immune markers, quality of life, and pruritus scores are incorporated to investigate mechanisms and potential biomarkers, aiming to generate robust clinical evidence that supports future development and clinical translation of hUC-MSC therapy for PBC.
Voluntary participation and signed informed consent.
Age 18 to 75 years, both genders.
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);
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).
Sequential
Standard background therapy
DrugUDCA capsule 250 mg, orally, 13-15 mg/kg/day, taken with a small amount of water. This background therapy is administered only to participants who have been on a stable dose of UDCA for at least 6 months prior to enrollment (and stable for ≥3 months before screening). Participants who are intolerant to UDCA (and have not used UDCA for ≥3 months before enrollment) do not receive UDCA during the study.
Placebo
DrugMatching placebo solution (e.g., 5% human serum albumin in 0.9% saline) administered via peripheral intravenous infusion at Week 0, Week 1, and Week 2 (once weekly for 3 infusions).
hUC-MSC Dose Level 1
Biological/VaccineHuman umbilical cord-derived mesenchymal stromal cells, planned at 1.5×10⁸ cells per infusion (final dose subject to confirmation based on phase I MTD/RP2D). Administered via peripheral intravenous infusion at Week 0, Week 1, and Week 2 (once weekly for 3 infusions).
hUC-MSC Dose Level 2
Biological/VaccineHuman umbilical cord-derived mesenchymal stromal cells, planned at 2.0×10⁸ cells per infusion (final dose subject to confirmation based on phase I MTD/RP2D). Administered via peripheral intravenous infusion at Week 0, Week 1, and Week 2 (once weekly for 3 infusions).
Incidence of Dose-Limiting Toxicity (DLT) in Phase I
Occurrence of DLT during the DLT observation period (single-dose cohort: 7 days after infusion; multiple-dose cohort: 28 days after first infusion), graded by CTCAE v6.0.
Incidence of Treatment-Emergent Adverse Events and Serious Adverse Events (Phase I)
Safety and tolerability assessed by monitoring TEAEs, SAEs, and clinically significant changes in vital signs, physical examination, laboratory parameters, and 12-lead ECG.
Maximum Tolerated Dose (MTD) of hUC-MSC in PBC Patients (Phase I)
Determination of MTD based on DLT occurrence in the 3+3 dose-escalation phase I; MTD is the highest dose with ≤1/6 participants experiencing DLT.
Composite Biochemical Response at Week 12 (Phase II)
Proportion of participants achieving all three: ALP \< 1.67×ULN, ALP reduction ≥15% from baseline, and total bilirubin ≤ ULN at Week 12.
Proportion with ALP <1.67×ULN or ALP Reduction ≥15% or TB ≤ULN at Week 12 (Phase I)
Exploratory efficacy endpoint for phase I - participants meeting at least one of the three criteria at Week 12.
Change from Baseline in Alkaline Phosphatase (ALP) (Phase I)
Absolute and percentage changes from baseline at each specified visit.
Change from Baseline in Total Bilirubin (TB) (Phase I)
Absolute and percentage changes from baseline at each specified visit.
Change from Baseline in Direct Bilirubin (DBIL) (Phase I)
Absolute and percentage changes from baseline at each specified visit.
Change from Baseline in Immunoglobulins (IgG, IgM) - (Phase I)
Exploratory immune function endpoint.
Change from Baseline in Lymphocyte Subsets (Phase II)
Exploratory immune markers including CD3⁺, CD4⁺, CD8⁺, CD4⁺/CD8⁺ ratio.
Change from Baseline in Cytokines (Phase II)
Exploratory cytokine marker including Interleukin-6 (IL-6), Interleukin-10 (IL-10), Tumor Necrosis Factor-α (TNF-α), and Interferon-γ (IFN-γ).
Change from Baseline in C-Reactive Protein (CRP) (Phase II)
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