Primary Biliary Cholangitis
Conditions
Brief summary
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.
Detailed description
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.
Interventions
DRUGStandard background therapy
UDCA 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.
DRUGPlacebo
Matching 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).
BIOLOGICALhUC-MSC Dose Level 1
Human 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).
BIOLOGICALhUC-MSC Dose Level 2
Human 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).
Sponsors
Beijing 302 Hospital
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
The phase I dose-escalation stage (3+3 design) is conducted first to determine the recommended phase II dose; after that, the phase II randomized, double-blind, placebo-controlled stage is initiated with three parallel arms.
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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: 1. Biochemical evidence of cholestasis (predominantly elevated ALP and GGT) with imaging excluding extrahepatic or intrahepatic large bile duct obstruction; 2. Positive for anti-mitochondrial antibody (AMA)/AMA-M2, or other PBC-specific autoantibodies (anti-gp210, anti-sp100); 3. 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: 1. Within 2 months before screening: fibrates and glitazones; 2. 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); 3. 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Dose-Limiting Toxicity (DLT) in Phase I | Up to Day 7 (single-dose) or up to Day 28 (multiple-dose). | 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) | Up to Day 7 (single-dose) or up to Day 28 (multiple-dose). | 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) | At completion of phase I dose escalation (after DLT evaluation). | 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) | Week 12 | Proportion of participants achieving all three: ALP \< 1.67×ULN, ALP reduction ≥15% from baseline, and total bilirubin ≤ ULN at Week 12. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion with ALP <1.67×ULN or ALP Reduction ≥15% or TB ≤ULN at Week 12 (Phase I) | Week 12 | 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) | Baseline, Day 3, Week 1, 2, 4, 12, 24, 48, 72, 96 | Absolute and percentage changes from baseline at each specified visit. |
| Change from Baseline in Total Bilirubin (TB) (Phase I) | Baseline, Day 3, Week 1, 2, 4, 12, 24, 48, 72, 96 | Absolute and percentage changes from baseline at each specified visit. |
| Change from Baseline in Direct Bilirubin (DBIL) (Phase I) | Baseline, Day 3, Week 1, 2, 4, 12, 24, 48, 72, 96 | Absolute and percentage changes from baseline at each specified visit. |
| Change from Baseline in Alanine Aminotransferase (ALT) (Phase I) | Baseline, Day 3, Week 1, 2, 4, 12, 24, 48, 72, 96. | Absolute and percentage changes from baseline. |
| Change from Baseline in Aspartate Aminotransferase (AST) (Phase I) | Baseline, Day 3, Week 1, 2, 4, 12, 24, 48, 72, 96. | Absolute and percentage changes from baseline. |
| Change from Baseline in Gamma-Glutamyl Transferase (GGT) (Phase I) | Baseline, Day 3, Week 1, 2, 4, 12, 24, 48, 72, 96. | Absolute and percentage changes from baseline. |
| Change from Baseline in Primary Biliary Cholangitis-40 (PBC-40) Total Score (Phase I) | Baseline, Day 3, Week 1, 2, 4, 12, 24, 48, 72, 96. | Scale range: 40-200; higher scores indicate worse disease-specific quality of life. |
| Change from Baseline in Pruritus Numerical Rating Scale (NRS) Score (Phase I) | Baseline, Day 3, Week 1, 2, 4, 12, 24, 48, 72, 96. | Scale range: 0-10; higher scores indicate worse itch severity. |
| Change from Baseline in Itchy Quality of Life (ItchyQoL) Total Score (Phase I) | Baseline, Day 3, Week 1, 2, 4, 12, 24, 48, 72, 96. | Scale range: 22-110; higher scores indicate worse itch-related quality of life. |
| Change from Baseline in Alkaline Phosphatase (ALP) (Phase II) | Baseline, Day 3, Week 1, 2, 4, 12, 24, 48, 72, 96. | Absolute and percentage changes from baseline at each specified visit. |
| Change from Baseline in Total Bilirubin (TB) (Phase II) | Baseline, Day 3, Week 1, 2, 4, 12, 24, 48, 72, 96. | Absolute and percentage changes from baseline at each specified visit. |
| Change from Baseline in Direct Bilirubin (DBIL) (Phase II) | Baseline, Day 3, Week 1, 2, 4, 12, 24, 48, 72, 96. | Absolute and percentage changes from baseline at each specified visit. |
| Change from Baseline in Alanine Aminotransferase (ALT) (Phase II) | Baseline, Day 3, Week 1, 2, 4, 12, 24, 48, 72, 96. | Absolute and percentage changes from baseline. |
| Change from Baseline in Aspartate Aminotransferase (AST) (Phase II) | Baseline, Day 3, Week 1, 2, 4, 12, 24, 48, 72, 96. | Absolute and percentage changes from baseline. |
| Change from Baseline in Gamma-Glutamyl Transferase (GGT) (Phase II) | Baseline, Day 3, Week 1, 2, 4, 12, 24, 48, 72, 96. | Absolute and percentage changes from baseline. |
| Change from Baseline in Primary Biliary Cholangitis-40 (PBC-40) Total Score (Phase II) | Baseline, Day 3, Week 1, 2, 4, 12, 24, 48, 72, 96 | Scale range: 40-200; higher scores indicate worse disease-specific quality of life. |
| Change from Baseline in Pruritus Numerical Rating Scale (NRS) Score (Phase II) | Baseline, Day 3, Week 1, 2, 4, 12, 24, 48, 72, 96 | Scale range: 0-10; higher scores indicate worse itch severity. |
| Change from Baseline in Itchy Quality of Life (ItchyQoL) Total Score (Phase II) | Baseline, Day 3, Week 1, 2, 4, 12, 24, 48, 72, 96 | Scale range: 22-110; higher scores indicate worse itch-related quality of life. |
| Change from Baseline in Serum Total Bile Acids (TBA) (Phase II) | Baseline, Day 3, Week 1, 2, 4, 12, 24, 48, 72, 96. | — |
| Change from Baseline in 7α-Hydroxy-4-cholesten-3-one (C4) (Phase II) | Baseline, Day 3, Week 1, 2, 4, 12, 24, 48, 72, 96. | — |
| Change from Baseline in Fibroblast Growth Factor 19 (FGF-19) (Phase II) | Baseline, Day 3, Week 1, 2, 4, 12, 24, 48, 72, 96. | — |
| Change from Baseline in Liver Stiffness by Transient Elastography (Phase II) | Baseline and Week 12. | Change in liver stiffness measurement (kPa) at Week 12. |
Countries
China
Contacts
CONTACTLei Shi, MD, PhD
CONTACTFu-Sheng Wang, MD, PhD
STUDY_CHAIRFu-Sheng Wang, MD, PhD
The Fifth Medical Center of PLAGeneral Hospital
Outcome results
None listed