Use of Bezafibrate in Patients With Primary Biliary Cirrhosis to Archive Complete Biochemical Response in Non-responders

Study Overview
=================
Brief Summary
-----------------
The primary biliary cholangitis (PBC), formerly known as primary biliary cirrhosis, treatment is based in the use of ursodeoxycholic acid (UDCA) at a daily dose of 13 to 15 mg/kg, without other treatment options. Patients with good or complete response to UDCA have more liver transplant-free survival and delay histologic progression compared to patients with partial or no response. Nowadays there is an estimated partial response to UDCA in approximately 30 to 50% of patients with PBC. There is a need for new second line management strategies for patients without a biochemical response to UDCA. The addition of bezafibrate to the treatment of PBC patients with partial biochemical response to UDCA, will increase the biochemical response and improve the long term prognosis? And if so, which are the efficacy and security of bezafibrate in PBC patients without biochemical response?

Detailed Description
-----------------
There are case reports and pilot studies in patients with primary biliary cholangitis (PBC) In the literature in which the effect of fibrates (specially bezafibrate) on the improvement of biochemical cholestasis have been seen, however the clinical benefit (survival, mortality, fatigue, pruritus) has not been reported and likewise the response criteria used in previous studies is very heterogeneous. In previous studies, bezafibrate has been proved to be a secure drug in this patients, with few adverse events, also it is an economic and of easy access drug. For all this the investigators intent to study the utility of bezafibrate as an additional treatment in PBC patients without response to UDCA. This is a randomized, placebo-controlled, parallel-group study designed to enroll a total of 34 patients with diagnosis of PBC without a complete response to the use of UDCA for more than a year, then the participants will be divided by randomization to receive bezafibrate or placebo, resulting in a total of two groups of 17 patients each. Both groups will be followed every 3 months for a total of 1 year with clinical and laboratory follow-up to determine the efficacy and security of the treatment. The investigators will measure all the laboratory variables related to the disease and possible adverse effects of the use of fibrates (creatine kinase, transaminases, bilirubin, alkaline phosphatase), also the investigators will measure the quality of life variables (pruritus severity, Short Form [SF]-36 questionnaire), and determine the fibrosis stage at the beginning and end of the study by non-invasive methods (transient elastography). The study is directed to patients with PBC diagnosis who have had management with standard UDCA dose (13 to 15 mg/kg per day) for at least 6 months and had not reached complete biochemical response, defined by Paris II criteria. The dose of fibrate to use will be bezafibrate 200 mg every 12 hours or placebo every 12 hours for 12 months, both having the exact characteristics to avoid their recognition. Patients will continue the administration of UDCA at the same dose at enrollment. The intervention will be for a period of 12 months, with a follow-up every 3 months completing 5 medical follow-up visits (0, 3, 6, 9 and 12 months).

Official Title
-----------------
Efficacy and Security of Bezafibrate in Patients With Primary Biliary Cirrhosis Without Biochemical Response to Ursodeoxycholic Acid: A Randomized, Double-blind, Placebo-controlled Trial

Conditions
-----------------
Primary Biliary Cirrhosis

Intervention / Treatment
-----------------
* Drug: Bezafibrate
* Drug: Ursodeoxycholic Acid
* Drug: Placebo (for Bezafibrate)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Primary biliary cirrhosis diagnosis made by 2 of the 3 criteria: Biochemical evidence of cholestasis with an alkaline phosphatase rise of 1.5 times the upper normal limit. Anti-mitochondrial antibodies positivity Histopathologic evidence of a nonsuppurative cholangitis and small bile ducts destruction Use of ursodeoxycholic acid (UDCA) for at least 6 months at enrollment at a therapeutic dose (13 to 15 mg per Kg per day) Evidence of a suboptimal biochemical response to UDCA, defined by the presence of one of the Paris II criteria: Alkaline phosphatase more or equal to 1.5 times the normal upper limit Aspartate transaminase more or equal to 1.5 times the normal upper limit Bilirubin more than 1 mg/dL Signed informed consent. Exclusion Criteria: No informed consent given to enrollment Actual or history of hepatic decompensation (ascitis, variceal upper gastrointestinal bleeding, hepatic encephalopathy) Secondary immunosuppression caused by drugs (for example; steroids), use of statins or fibrates in the last 6 months. The investigators will exclude patients with medical indication of statin use. Coexistence of hepatopathy, chronic viral infections like C hepatitis virus, B virus and HIV. Excessive alcohol intake, autoimmune hepatitis, non-alcoholic fatty liver disease (diagnosed by histopathology), Wilson disease, hemochromatosis, celiac disease, choledocolithiasis, non-controlled thyroid disease Post liver transplant Known allergy or intolerance to fibrates Pregnancy or women who desire to become pregnant Chronic kidney disease with a glomerular filtration less than 60 ml/min Patients under total anticoagulation with vitamin K antagonist

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bezafibrate & Ursodeoxycholic acid<br>Bezafibrate 200 mg capsule every 12 hours and ursodeoxycholic acid at a dose of 13 to 15 mg per Kg per day, for 12 months | Drug: Bezafibrate<br>* Bezafibrate 200 mg manufactured in a pill/capsule presentation<br>* Other names: Bezalip;Drug: Ursodeoxycholic Acid<br>* The patients will continue with the administration of ursodeoxycholic acid at a dose of 13 to 15 mg per Kg per day throughout the study<br>* Other names: Ursofalk;|
| Placebo Comparator: Placebo & Ursodeoxycholic acid<br>Placebo capsule (for bezafibrate 200 mg capsule) every 12 hours and ursodeoxycholic acid at a dose of 13 to 15 mg per Kg per day, for 12 months | Drug: Ursodeoxycholic Acid<br>* The patients will continue with the administration of ursodeoxycholic acid at a dose of 13 to 15 mg per Kg per day throughout the study<br>* Other names: Ursofalk;Drug: Placebo (for Bezafibrate)<br>* Starch pill/capsule manufactured to mimic bezafibrate 200 mg tablet<br>* Other names: Does not apply;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete biochemical response | The complete biochemical response in patients with primary biliary cholangitis is defined as the reduction of alkaline phosphatase lower than 1.5 times the upper normal limit, reduction of aspartate transaminase lower than 1.5 times the upper normal limit and bilirubin lower than 1 mg/dL | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Increase in liver transaminases or development of rhabdomyolysis | Elevation of transaminases of biochemical evidence of rhabdomyolysis. | Follow-up every 3 months for 12 months. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Primary Biliary Cirrhosis, Primary Biliary Cholangitis, Bezafibrate, Ursodeoxycholic acid