Fenofibrate Combined With Ursodeoxycholic Acid in Subjects With Primary Biliary Cholangitis

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

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.

Study Overview

• Status: Recruiting
• Conditions: Primary Biliary Cholangitis
• Intervention / Treatment: Drug: Placebo Combined With Ursodeoxycholic Acid; Drug: Fenofibrate Combined With Ursodeoxycholic Acid

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 150
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Ying Han; Phone Number: +86-29-84771539; Email: hanying1@fmmu.edu.cn
• Study Contact Backup: Name: Yulong Shang; Phone Number: +86 18629661032; Email: shangyl870222@163.com

Study Locations

• China
  • Shaanxi
    • Xi'an, Shaanxi, China, 710032
      • Recruiting
      • Ying han
      • Contact: Ying Han; Phone Number: +86-29-84771539; Email: hanying1@fmmu.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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 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 creatine kinase	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
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 Blood urea nitrogen	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

Collaborators and Investigators

• Sponsor: Xijing Hospital of Digestive Diseases
• Investigators: Principal Investigator: Ying Han, Doctor, Xijing hospital, Air force Military Medical University

Study record dates

Study Major Dates

• Study Start (Actual): February 22, 2023
• Primary Completion (Anticipated): December 1, 2024
• Study Completion (Anticipated): December 1, 2025

Study Registration Dates

• First Submitted: December 13, 2022
• First Submitted That Met QC Criteria: February 20, 2023
• First Posted (Actual): March 2, 2023

Study Record Updates

• Last Update Posted (Estimate): March 6, 2023
• Last Update Submitted That Met QC Criteria: March 3, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Liver Diseases; Fibrosis; Biliary Tract Diseases; Bile Duct Diseases; Cholestasis, Intrahepatic; Cholestasis; Liver Cirrhosis; Cholangitis; Liver Cirrhosis, Biliary; Molecular Mechanisms of Pharmacological Action; Antimetabolites; Gastrointestinal Agents; Hypolipidemic Agents; Lipid Regulating Agents; Cholagogues and Choleretics; Fenofibrate; Ursodeoxycholic Acid
• Other Study ID Numbers: KY20222274-C-1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No