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

Primary Purpose

Primary Biliary Cirrhosis

Status
Unknown status
Phase
Phase 3
Locations
Mexico
Study Type
Interventional
Intervention
Bezafibrate
Ursodeoxycholic Acid
Placebo (for Bezafibrate)
Sponsored by
Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Primary Biliary Cirrhosis focused on measuring Primary Biliary Cirrhosis, Primary Biliary Cholangitis, Bezafibrate, Ursodeoxycholic acid

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Instituto Nacional de Ciencias Medicas y Nutricion Salvador ZubiranRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Bezafibrate & Ursodeoxycholic acid

Placebo & Ursodeoxycholic acid

Arm Description

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

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

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

Increase in liver transaminases or development of rhabdomyolysis
Elevation of transaminases of biochemical evidence of rhabdomyolysis.

Full Information

First Posted
October 13, 2016
Last Updated
April 19, 2018
Sponsor
Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
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1. Study Identification

Unique Protocol Identification Number
NCT02937012
Brief Title
Use of Bezafibrate in Patients With Primary Biliary Cirrhosis to Archive Complete Biochemical Response in Non-responders
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
Study Type
Interventional

2. Study Status

Record Verification Date
April 2018
Overall Recruitment Status
Unknown status
Study Start Date
October 2016 (undefined)
Primary Completion Date
April 2019 (Anticipated)
Study Completion Date
December 2019 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Primary Biliary Cirrhosis
Keywords
Primary Biliary Cirrhosis, Primary Biliary Cholangitis, Bezafibrate, Ursodeoxycholic acid

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
34 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Bezafibrate & Ursodeoxycholic acid
Arm Type
Experimental
Arm Description
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
Arm Title
Placebo & Ursodeoxycholic acid
Arm Type
Placebo Comparator
Arm Description
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
Intervention Type
Drug
Intervention Name(s)
Bezafibrate
Other Intervention Name(s)
Bezalip
Intervention Description
Bezafibrate 200 mg manufactured in a pill/capsule presentation
Intervention Type
Drug
Intervention Name(s)
Ursodeoxycholic Acid
Other Intervention Name(s)
Ursofalk
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
Placebo (for Bezafibrate)
Other Intervention Name(s)
Does not apply
Intervention Description
Starch pill/capsule manufactured to mimic bezafibrate 200 mg tablet
Primary Outcome Measure Information:
Title
Complete biochemical response
Description
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
Time Frame
12 months
Secondary Outcome Measure Information:
Title
Increase in liver transaminases or development of rhabdomyolysis
Description
Elevation of transaminases of biochemical evidence of rhabdomyolysis.
Time Frame
Follow-up every 3 months for 12 months.
Other Pre-specified Outcome Measures:
Title
Comparison of fatigue between groups
Description
Clinical evaluation of fatigue with the use of the Krupp´s Fatigue Severity Scale.
Time Frame
Two evaluations: At enrollment and 12 months later.
Title
Quality of life
Description
Evaluation of the quality of life with the SF-36 questionnaire.
Time Frame
Two evaluations: At enrollment and 12 months later.
Title
Pruritus intensity
Description
Evaluation made by the use of visual analogue scales.
Time Frame
Follow-up every 3 months for 12 months.
Title
Liver fibrosis evaluation by a non-invasive method
Description
Evaluation of the liver fibrosis by transient elastography.
Time Frame
Two evaluations: At enrollment and 12 months later.
Title
Disease natural history outcome
Description
Compare the liver transplant-free survival, overall survival and liver decompensation-free survival between groups.
Time Frame
Two evaluations: At enrollment and 12 months later.
Title
Prognostic scales comparison
Description
Compare the different prognostic scales (Mayo, Child-Pugh and MELD) between groups.
Time Frame
Two evaluations: At enrollment and 12 months later.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Edgardo Eric Lopez Mendez, MD
Phone
(52)(55)54870900
Ext
2710
Email
ericlopezmendez@yahoo.com.mx
First Name & Middle Initial & Last Name or Official Title & Degree
Sergio Gabriel Munoz Martinez, MD
Phone
(52)(55)54870900
Ext
2710
Email
sergio_sg@hotmail.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Edgardo Eric Lopez Mendez, MD
Organizational Affiliation
Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
Official's Role
Principal Investigator
Facility Information:
Facility Name
Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
City
Mexico City
ZIP/Postal Code
14000
Country
Mexico
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Edgardo Eric Lopez Mendez, MD
Phone
(01)(55) 54870900
Ext
2710
Email
ericlopezmendez@yahoo.com.mx
First Name & Middle Initial & Last Name & Degree
Sergio Gabriel Munoz Martinez, MD
Phone
(01)(55) 54870900
Ext
2710
Email
sergio_sg@hotmail.com
First Name & Middle Initial & Last Name & Degree
Edgardo Eric Lopez Martinez, MD
First Name & Middle Initial & Last Name & Degree
Sergio Gabriel Munoz Martinez, MD
First Name & Middle Initial & Last Name & Degree
Ignacio Garcia Juarez, MD
First Name & Middle Initial & Last Name & Degree
Ernesto Marquez Guillen, MD
First Name & Middle Initial & Last Name & Degree
Carlos Moctezuma Velazquez, MD
First Name & Middle Initial & Last Name & Degree
Alejandra Tepox Padron, MD

12. IPD Sharing Statement

Plan to Share IPD
Undecided
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URL
http://www.ingentaconnect.com/contentone/springer/hhci/2010/00000008/00000004/art00006
Description
Krupp´s Fatigue Severity Scale taken from the article: Valencia-Flores, et al. Sleep, Fatigue, Depression, and Pain in Mexican Women with Systemic Lupus Erythematosus: An Exploratory Study. Hisp Health Care Int. 2010

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

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