Fenofibrate Combined With Ursodeoxycholic Acid in Subjects With Primary Biliary Cholangitis

Study Overview
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Brief Summary
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Current treatment guidelines recommend ursodeoxycholic acid (UDCA) as the first-line treatment for new-diagnosed primary biliary cholangitis (PBC) patients. However, up to 40% patients are insensitive to UDCA monotherapy, and evaluation of UDCA response at 12 months may result in long period of ineffective treatment. We aimed to develop a new criterion to reliably identify non-response patients much earlier. Recently, our team designed and validated a new early criterion for distinguishing high-risk PBC patients in a Chinese population for the first time. Our data indicated that PBC patients with ALP ≤ 2.5 × ULN, AST ≤ 2 × ULN, and TBIL ≤ 1 × ULN (Xi'an criterion) after 1 month UDCA treatment were likely to have better prognosis. It can be readily applied in the rapid identification of PBC patients who require additional therapeutic approaches. However, whether it is reasonable to apply it to the response definition of clinical research, and the guidance of PBC management and choice of second-line treatment, further research is needed.

Detailed Description
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This is a multi-center, randomized, placebo-controlled, parallel-group study that will assess the efficacy and safety of fenofibrate in patients with PBC who had an inadequate biochemical response to UDCA, as defined by the Xi'an criteria. Fenofibrate or placebo 200 mg will be daily administered in combination with UDCA 13-15 mg/kg/d for 48 months. Patient safety will be monitored. Primary end-point will be the percentage of patients with a complete normalization of the ALP and TBIL. Secondary endpoints will include the percentage of drug-related adverse events, survival rates without liver transplantation or liver decompensation, time course of non-invasive liver fibrosis measurements (LSM), time course of endoscopic, ultrasound, and biochemical features of portal hypertension, time course of pruritus and of quality of life using validated scales.

Official Title
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A Prospective, Multi-center, Randomized, Double-blind, Placebo-controlled Study: Fenofibrate Combined With Ursodeoxycholic Acid in Subjects With Primary Biliary Cholangitis and an Inadequate Response to Ursodeoxycholic Acid

Conditions
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Primary Biliary Cholangitis

Intervention / Treatment
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* Drug: Placebo Combined With Ursodeoxycholic Acid
* Drug: Fenofibrate Combined With Ursodeoxycholic Acid


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must have provided written informed consent; Age 18-75 years; BMI 17-28 kg/m2 Male or female with a diagnosis of PBC, by at least two of the following criteria: History of AP above ULN for at least six months; Positive AMA titers (>1/40 on immunofluorescence or M2 positive by enzyme linked immunosorbent assay (ELISA) or positive PBC-specific antinuclear antibodies; Documented liver biopsy result consistent with PBC. Incomplete response to UDCA defined by Xi'an criteria (ALP >2.5× ULN, AST>2×ULN or TBIL>1×ULN) after UDCA treatment for 4-6 weeks with at least one abnormal test in ALP or TBIL. Exclusion Criteria: History or presence of other concomitant liver diseases. ALT/AST > 5×ULN, TBIL > 3×ULN. If female: known pregnancy, or has a positive urine pregnancy test (confirmed by a positive serum pregnancy test), or lactating. Allergic to fenofibrate or ursodeoxycholic acid. Taking hepatotoxic drugs (e.g., dapsone, erythromycin, fluconazole, ketoconazole, rifampicin) for more than 2 weeks within 6 months, and long-term hormonal users. Recurrent variceal bleeding, poorly controlled hepatic encephalopathy or refractory ascites. Patients with a history of severe cardiac, cerebrovascular, renal, respiratory disease or functional failure, and psychiatric disorders (including those due to alcohol and drug abuse). Creatinine >1.5×ULN and creatinine clearance <60 ml/min. Currently using statins (such as pravastatin, fluvastatin, and simvastatin), other fibrates (such as gemfibrozil and bezafibrate), and drugs structurally similar to fenofibrate (like ketoprofen). Planned to receive an organ transplant or an organ transplant recipient. Needing Liver transplantation within 1 year according to the Mayo Rick score. Any other condition(s) that would compromise the safety of the subject or compromise the quality of the clinical study, as judged by the Investigator.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>1 tablet/ day | Drug: Placebo Combined With Ursodeoxycholic Acid<br>* 1 tablet/ day<br>* Other names: UDCA 13-15mg/kg/d;|
| Experimental: Fenofibrate<br>200 mg/day | Drug: Fenofibrate Combined With Ursodeoxycholic Acid<br>* 200 mg/day<br>* Other names: UDCA 13-15mg/kg/d;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of patients with complete biochemical response | The normalisation of Alkaline Phosphatase (ALP) and total bilirubin (TBIL). | 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of patients having complete biochemical response | The normalisation of Alkaline Phosphatase (ALP) and total bilirubin (TBIL) at 4, 12, 24, and 36 weeks. | 4, 12, 24, 36, and 48 weeks | 
| Assessment of the fatigue and the quality of life | Change from baseline in primary biliary cholangitis -40 (PBC-40) quality of life (QoL) questionnaire scores. | 4, 12, 24, 36, and 48 weeks | 
| Assessment of the fatigue and the quality of life | Change from baseline in pruritus as assessed by Visual Analogue Scale (VAS) total score for fatigue and pruritus. | 4, 12, 24, 36, and 48 weeks | 
| Evolution of the biological markers of the hepatic function or being in the usual prognostic scores | Mayo score at 4, 12, 24, 36, and 48 weeks | 4, 12, 24, 36, and 48 weeks | 
| Evolution of the biological markers of the hepatic function or being in the usual prognostic scores | Child-Puch score at 4, 12, 24, 36, and 48 weeks | 4, 12, 24, 36, and 48 weeks | 
| Evolution of the biological markers of the hepatic function or being in the usual prognostic scores | MELD score at 4, 12, 24, 36, and 48 weeks | 4, 12, 24, 36, and 48 weeks | 
| Evolution of the biological markers of the hepatic function or being in the usual prognostic scores | GLOBE-PBC score at 48 weeks | 48 weeks | 
| Evolution of the biological markers of the hepatic function or being in the usual prognostic scores | UK-PBC score at 48 weeks | 48 weeks | 
| Percentage of patients having biological or clinical adverse events | Increase of creatinine | 4, 12, 24, 36, and 48 weeks | 
| Percentage of patients having biological or clinical adverse events | Increase of Blood urea nitrogen | 4, 12, 24, 36, and 48 weeks | 
| Percentage of patients having biological or clinical adverse events | Increase of creatine kinase | 4, 12, 24, 36, and 48 weeks | 
| Percentage of patients having biological or clinical adverse events | Increase of ALT and AST. | 4, 12, 24, 36, and 48 weeks | 
| Survival without transplantation and hepatic impairment | Occurrence of ascites, variceal bleeding, hepatic encephalopathy, liver-transplantation, or death. | 48 weeks |