Clinical trial NCT05751967: Fenofibrate Combined with Ursodeoxycholic Acid in Subjects with Primary Biliary Cholangitis
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Primary Biliary Cholangitis
Lead sponsor: Xijing Hospital of Digestive Diseases
Sponsor class: OTHER
First posted: 2023-03-02
Enrollment: 150
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Percentage of patients with complete biochemical response
timeFrame: 48 weeks
Secondary outcomes:
measure: Percentage of patients having complete biochemical response
timeFrame: 4, 12, 24, 36, and 48 weeks
measure: Assessment of the fatigue and the quality of life
timeFrame: 4, 12, 24, 36, and 48 weeks
measure: Assessment of the fatigue and the quality of life
timeFrame: 4, 12, 24, 36, and 48 weeks
measure: Evolution of the biological markers of the hepatic function or being in the usual prognostic scores
timeFrame: 4, 12, 24, 36, and 48 weeks
measure: Evolution of the biological markers of the hepatic function or being in the usual prognostic scores
timeFrame: 4, 12, 24, 36, and 48 weeks
measure: Evolution of the biological markers of the hepatic function or being in the usual prognostic scores
timeFrame: 4, 12, 24, 36, and 48 weeks
measure: Evolution of the biological markers of the hepatic function or being in the usual prognostic scores
timeFrame: 48 weeks
measure: Evolution of the biological markers of the hepatic function or being in the usual prognostic scores
timeFrame: 48 weeks
measure: Percentage of patients having biological or clinical adverse events
timeFrame: 4, 12, 24, 36, and 48 weeks
measure: Percentage of patients having biological or clinical adverse events
timeFrame: 4, 12, 24, 36, and 48 weeks
measure: Percentage of patients having biological or clinical adverse events
timeFrame: 4, 12, 24, 36, and 48 weeks
measure: Percentage of patients having biological or clinical adverse events
timeFrame: 4, 12, 24, 36, and 48 weeks
measure: Survival without transplantation and hepatic impairment
timeFrame: 48 weeks
Other outcomes:
Locations:
city: Lanzhou
country: China
facility: The second hospital of Lanzhou University
state: Gansu
city: Nanjing
country: China
facility: Nanjing Drum Tower Hospital
state: Jiangsu
city: Xi'an
country: China
facility: Ying han
state: Shaanxi
city: Chengdu
country: China
facility: Sichuan Provincial People's Hospital,
state: Sichuan
city: Tianjin
country: China
facility: Tianjin Medical University General Hospital
Study officials:
affiliation: The First Affiliated Hospital of Air Force Medicial University
name: Ying Han, Doctor
role: PRINCIPAL_INVESTIGATOR
References: