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

April 19, 2018 updated by: Eric Lopez Mendez, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran

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

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?

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

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).

Study Type

Interventional

Enrollment (Anticipated)

34

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

  • Name: Sergio Gabriel Munoz Martinez, MD
  • Phone Number: 2710 (52)(55)54870900
  • Email: sergio_sg@hotmail.com

Study Locations

  • Mexico
      • Mexico City, Mexico, 14000
        • Recruiting
        • Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
        • Contact:
        • Contact:
        • Principal Investigator:
          • Edgardo Eric Lopez Martinez, MD
        • Sub-Investigator:
          • Sergio Gabriel Munoz Martinez, MD
        • Sub-Investigator:
          • Ignacio Garcia Juarez, MD
        • Sub-Investigator:
          • Ernesto Marquez Guillen, MD
        • Sub-Investigator:
          • Carlos Moctezuma Velazquez, MD
        • Sub-Investigator:
          • Alejandra Tepox Padron, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Primary biliary cirrhosis diagnosis made by 2 of the 3 criteria:

    1. Biochemical evidence of cholestasis with an alkaline phosphatase rise of 1.5 times the upper normal limit.
    2. Anti-mitochondrial antibodies positivity
    3. 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:

    1. Alkaline phosphatase more or equal to 1.5 times the normal upper limit
    2. Aspartate transaminase more or equal to 1.5 times the normal upper limit
    3. 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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Bezafibrate & Ursodeoxycholic acid
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
Bezafibrate 200 mg manufactured in a pill/capsule presentation
Other Names:
  • Bezalip
Drug: Ursodeoxycholic Acid
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
Other Names:
  • Ursofalk
Placebo Comparator: Placebo & Ursodeoxycholic acid
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
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
Other Names:
  • Ursofalk
Drug: Placebo (for Bezafibrate)
Starch pill/capsule manufactured to mimic bezafibrate 200 mg tablet
Other Names:
  • Does not apply

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Complete biochemical response
Time Frame: 12 months
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
Time Frame: Follow-up every 3 months for 12 months.
Elevation of transaminases of biochemical evidence of rhabdomyolysis.
Follow-up every 3 months for 12 months.

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Comparison of fatigue between groups
Time Frame: Two evaluations: At enrollment and 12 months later.
Clinical evaluation of fatigue with the use of the Krupp´s Fatigue Severity Scale.
Two evaluations: At enrollment and 12 months later.
Quality of life
Time Frame: Two evaluations: At enrollment and 12 months later.
Evaluation of the quality of life with the SF-36 questionnaire.
Two evaluations: At enrollment and 12 months later.
Pruritus intensity
Time Frame: Follow-up every 3 months for 12 months.
Evaluation made by the use of visual analogue scales.
Follow-up every 3 months for 12 months.
Liver fibrosis evaluation by a non-invasive method
Time Frame: Two evaluations: At enrollment and 12 months later.
Evaluation of the liver fibrosis by transient elastography.
Two evaluations: At enrollment and 12 months later.
Disease natural history outcome
Time Frame: Two evaluations: At enrollment and 12 months later.
Compare the liver transplant-free survival, overall survival and liver decompensation-free survival between groups.
Two evaluations: At enrollment and 12 months later.
Prognostic scales comparison
Time Frame: Two evaluations: At enrollment and 12 months later.
Compare the different prognostic scales (Mayo, Child-Pugh and MELD) between groups.
Two evaluations: At enrollment and 12 months later.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran

Investigators

  • Principal Investigator: Edgardo Eric Lopez Mendez, MD, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

October 1, 2016

Primary Completion (Anticipated)

April 1, 2019

Study Completion (Anticipated)

December 1, 2019

Study Registration Dates

First Submitted

October 13, 2016

First Submitted That Met QC Criteria

October 14, 2016

First Posted (Estimate)

October 18, 2016

Study Record Updates

Last Update Posted (Actual)

April 23, 2018

Last Update Submitted That Met QC Criteria

April 19, 2018

Last Verified

April 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 1757

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Undecided

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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