A Study of TQA3526 in the Treatment of Primary Biliary Cirrhosis (PBC)

Study Overview
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Brief Summary
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TQA3526 is a modified bile acid and FXR agonist. FXR is a key regulator of bile acid synthesis and transport. Bile acids are used by the body to help with digestion. It is hypothesized that regular treatment with TQA3526 will improve liver function in persons with Primary Biliary Cirrhosis (PBC).

Official Title
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A Phase IIa, Randomized, Double-blind, Placebo-controlled Study of TQA3526 in the Treatment of Naive or Previously Treated PBC Patients

Conditions
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Primary Biliary Cirrhosis

Intervention / Treatment
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* Drug: TQA3526
* Drug: Placebo to match TQA3526


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1.18 and 70 years old, male or female. 2.Proven as PBC, as demonstrated by the patient presenting with at least 2 of the following 3 diagnostic factors: History of increased ALP levels for at least 3 months prior to Day 0 in previously treated PBC patients，or ALP levels increased during screening in treatment naive PBC patients； ② Positive AMA titer (>1:40 titer on immunofluorescence or M2 positive by ELISA) or PBC-specific antinuclear antibodies (anti-GP210 and anti-SP100 positive)； ③ Liver biopsy consistent with PBC within 24W prior to randomization； 3.ALP value between 1.67 and 10 × ULN; 4.Taking ursodeoxycholic acid (UDCA) for at least 12 months (stable dose for ≥ 3 months) prior to Day 0, or unable to tolerate UDCA (no UDCA for ≥ 3 months) prior to Day 0. Exclusion Criteria: 1.Has other virus infected ; 2.History or presence of other concomitant liver diseases； 3.Presence of clinical complications of PBC or clinically significant hepatic decompensation； 4.Child-pugh grade B or C in patients with cirrhosis； 5.Creatinine (Cr) ≥1.5 times the upper limit of normal value and serum creatinine clearance rate <60mL/min； 6.ALT or AST>5×ULN；TBil>3×ULN； 7.Patients with a history of severe pruritus within 2 months prior to day 0; 8.History or presence of clinically concerning cardiac arrhythmias, the duration of the study may affect survival; 9.Presence of any other disease or condition that is interfering with the absorption, distribution, metabolism, or excretion of drugs including bile salt metabolism in the intestine; 10.Medical conditions that may cause nonhepatic increases in ALP (e.g., Paget's disease) or which may diminish life expectancy to < 2 years.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Climbing group<br> | Drug: TQA3526<br>* Tablet(s) administered orally once daily<br>Drug: Placebo to match TQA3526<br>* Tablet(s) administered orally once daily<br>|
| Experimental: Titration group<br> | Drug: TQA3526<br>* Tablet(s) administered orally once daily<br>Drug: Placebo to match TQA3526<br>* Tablet(s) administered orally once daily<br>|
| Experimental: Extension group<br> | Drug: TQA3526<br>* Tablet(s) administered orally once daily<br>Drug: Placebo to match TQA3526<br>* Tablet(s) administered orally once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Alkaline phosphatase (ALP) | The reduction of ALP level from baseline to 24 weeks. | Baseline up to 24w | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Liver function：ALP (excluding 12W/24W), ALT, AST, GGT, TBA and Tbil | The reduction of ALP , ALT, AST, GGT, TBA and Tbil from baseline to each time point. | Baseline up to 2, 4, 8, 12, 14, 16, 20, 24 weeks | 
| Fasting lipid：LDL-C、HDL-C、TG and TC | The rate of change of LDL-C、HDL-C、TG and TC from baseline to each time point. | Baseline up to 2, 4, 8, 12, 14, 16, 20, 24 weeks | 
| Cmax | Maximum concentration of the analyte in plasma. | predose, Weeks 2, 4, 8, 12, 14, 16, 20, 24 : 0, 1.5, 3.5 hours following drug administration | 
| tmax | Time from dosing to maximum concentration | predose, Weeks 2, 4, 8, 12, 14, 16, 20, 24 : 0, 1.5, 3.5 hours following drug administration | 
| AUC0-∞ | Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity | predose, Weeks 2, 4, 8, 12, 14, 16, 20, 24 : 0, 1.5, 3.5 hours following drug administration | 
| pharmacodynamics | The rate of change of FGF-19、C4、IgG and IgM from baseline to each time point. | Baseline up to 2, 4, 8, 12, 14, 16, 20, 24 weeks | 
| safety and tolerability: incidence of treatment emergent adverse events and serious treatment emergent adverse events | Evaluate safety and tolerability as assessed by the incidence of treatment emergent adverse events and serious treatment emergent adverse events comparing TQA3526 to placebo. | Baseline up to 2, 4, 8, 12, 14, 16, 20, 24 weeks |