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
Overview
- Phase
- Phase 3
- Status
- Recruiting
- Sponsor
- Xijing Hospital of Digestive Diseases
- Enrollment
- 150
- Locations
- 8
- Primary Endpoint
- Percentage of patients with complete biochemical response
Overview
Brief Summary
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
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 Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Prevention
- Masking
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Eligibility Criteria
- Ages
- 18 Years to 75 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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.
Arms & Interventions
Placebo
1 tablet/ day
Intervention: Placebo Combined With Ursodeoxycholic Acid (Drug)
Fenofibrate
200 mg/day
Intervention: Fenofibrate Combined With Ursodeoxycholic Acid (Drug)
Outcomes
Primary Outcomes
Percentage of patients with complete biochemical response
Time Frame: 48 weeks
The normalisation of Alkaline Phosphatase (ALP) and total bilirubin (TBIL).
Secondary Outcomes
- Survival without transplantation and hepatic impairment(48 weeks)
- Percentage of patients having complete biochemical response(4, 12, 24, 36, and 48 weeks)
- Assessment of the fatigue and the quality of life(4, 12, 24, 36, and 48 weeks)
- Evolution of the biological markers of the hepatic function or being in the usual prognostic scores(48 weeks)
- Percentage of patients having biological or clinical adverse events(4, 12, 24, 36, and 48 weeks)
- Evolution of the biological markers of the hepatic function or being in the usual prognostic scores(4, 12, 24, 36, and 48 weeks)
Investigators
Han Ying
Professor
Xijing Hospital of Digestive Diseases