- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02937012
Use of Bezafibrate in Patients With Primary Biliary Cirrhosis to Archive Complete Biochemical Response in Non-responders
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
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
Enrollment (Anticipated)
Phase
- Phase 3
Contacts and Locations
Study Contact
- Name: Edgardo Eric Lopez Mendez, MD
- Phone Number: 2710 (52)(55)54870900
- Email: ericlopezmendez@yahoo.com.mx
Study Contact Backup
- Name: Sergio Gabriel Munoz Martinez, MD
- Phone Number: 2710 (52)(55)54870900
- Email: sergio_sg@hotmail.com
Study Locations
-
-
-
Mexico City, Mexico, 14000
- Recruiting
- Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
-
Contact:
- Edgardo Eric Lopez Mendez, MD
- Phone Number: 2710 (01)(55) 54870900
- Email: ericlopezmendez@yahoo.com.mx
-
Contact:
- Sergio Gabriel Munoz Martinez, MD
- Phone Number: 2710 (01)(55) 54870900
- Email: sergio_sg@hotmail.com
-
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
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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
Study Plan
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
|
Bezafibrate 200 mg manufactured in a pill/capsule presentation
Other Names:
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:
|
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
|
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:
Starch pill/capsule manufactured to mimic bezafibrate 200 mg tablet
Other Names:
|
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.
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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.
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Liver fibrosis evaluation by a non-invasive method
Time Frame: Two evaluations: At enrollment and 12 months later.
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Evaluation of the liver fibrosis by transient elastography.
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Two evaluations: At enrollment and 12 months later.
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Disease natural history outcome
Time Frame: Two evaluations: At enrollment and 12 months later.
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Compare the liver transplant-free survival, overall survival and liver decompensation-free survival between groups.
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Two evaluations: At enrollment and 12 months later.
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Prognostic scales comparison
Time Frame: Two evaluations: At enrollment and 12 months later.
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Compare the different prognostic scales (Mayo, Child-Pugh and MELD) between groups.
|
Two evaluations: At enrollment and 12 months later.
|
Collaborators and Investigators
Investigators
- Principal Investigator: Edgardo Eric Lopez Mendez, MD, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
Publications and helpful links
General Publications
- Flores A, Mayo MJ. Primary biliary cirrhosis in 2014. Curr Opin Gastroenterol. 2014 May;30(3):245-52. doi: 10.1097/MOG.0000000000000058.
- Lindor KD, Gershwin ME, Poupon R, Kaplan M, Bergasa NV, Heathcote EJ; American Association for Study of Liver Diseases. Primary biliary cirrhosis. Hepatology. 2009 Jul;50(1):291-308. doi: 10.1002/hep.22906. No abstract available.
- Selmi C, Invernizzi P, Keeffe EB, Coppel RL, Podda M, Rossaro L, Ansari AA, Gershwin ME. Epidemiology and pathogenesis of primary biliary cirrhosis. J Clin Gastroenterol. 2004 Mar;38(3):264-71. doi: 10.1097/00004836-200403000-00013. Erratum In: J Clin Gastroenterol. 2004 May-Jun;38(5):following table of contents. Keefe EB [corrected to Keeffe EB].
- Boonstra K, Beuers U, Ponsioen CY. Epidemiology of primary sclerosing cholangitis and primary biliary cirrhosis: a systematic review. J Hepatol. 2012 May;56(5):1181-1188. doi: 10.1016/j.jhep.2011.10.025. Epub 2012 Jan 13.
- Jones DE, Bhala N, Burt J, Goldblatt J, Prince M, Newton JL. Four year follow up of fatigue in a geographically defined primary biliary cirrhosis patient cohort. Gut. 2006 Apr;55(4):536-41. doi: 10.1136/gut.2005.080317. Epub 2005 Nov 18.
- van Os E, van den Broek WW, Mulder PG, ter Borg PC, Bruijn JA, van Buuren HR. Depression in patients with primary biliary cirrhosis and primary sclerosing cholangitis. J Hepatol. 2007 Jun;46(6):1099-103. doi: 10.1016/j.jhep.2007.01.036. Epub 2007 Mar 2.
- Talwalkar JA, Souto E, Jorgensen RA, Lindor KD. Natural history of pruritus in primary biliary cirrhosis. Clin Gastroenterol Hepatol. 2003 Jul;1(4):297-302.
- Prince M, Chetwynd A, Newman W, Metcalf JV, James OF. Survival and symptom progression in a geographically based cohort of patients with primary biliary cirrhosis: follow-up for up to 28 years. Gastroenterology. 2002 Oct;123(4):1044-51. doi: 10.1053/gast.2002.36027.
- Springer J, Cauch-Dudek K, O'Rourke K, Wanless IR, Heathcote EJ. Asymptomatic primary biliary cirrhosis: a study of its natural history and prognosis. Am J Gastroenterol. 1999 Jan;94(1):47-53. doi: 10.1111/j.1572-0241.1999.00770.x.
- Shi J, Wu C, Lin Y, Chen YX, Zhu L, Xie WF. Long-term effects of mid-dose ursodeoxycholic acid in primary biliary cirrhosis: a meta-analysis of randomized controlled trials. Am J Gastroenterol. 2006 Jul;101(7):1529-38. doi: 10.1111/j.1572-0241.2006.00634.x.
- Poupon RE, Bonnand AM, Chretien Y, Poupon R. Ten-year survival in ursodeoxycholic acid-treated patients with primary biliary cirrhosis. The UDCA-PBC Study Group. Hepatology. 1999 Jun;29(6):1668-71. doi: 10.1002/hep.510290603.
- ter Borg PC, Schalm SW, Hansen BE, van Buuren HR; Dutch PBC Study Group. Prognosis of ursodeoxycholic Acid-treated patients with primary biliary cirrhosis. Results of a 10-yr cohort study involving 297 patients. Am J Gastroenterol. 2006 Sep;101(9):2044-50. doi: 10.1111/j.1572-0241.2006.00699.x. Epub 2006 Jul 18.
- Pares A, Caballeria L, Rodes J. Excellent long-term survival in patients with primary biliary cirrhosis and biochemical response to ursodeoxycholic Acid. Gastroenterology. 2006 Mar;130(3):715-20. doi: 10.1053/j.gastro.2005.12.029.
- Angulo P, Batts KP, Therneau TM, Jorgensen RA, Dickson ER, Lindor KD. Long-term ursodeoxycholic acid delays histological progression in primary biliary cirrhosis. Hepatology. 1999 Mar;29(3):644-7. doi: 10.1002/hep.510290301.
- Corpechot C. Primary biliary cirrhosis and bile acids. Clin Res Hepatol Gastroenterol. 2012 Sep;36 Suppl 1:S13-20. doi: 10.1016/S2210-7401(12)70016-5.
- Corpechot C, Abenavoli L, Rabahi N, Chretien Y, Andreani T, Johanet C, Chazouilleres O, Poupon R. Biochemical response to ursodeoxycholic acid and long-term prognosis in primary biliary cirrhosis. Hepatology. 2008 Sep;48(3):871-7. doi: 10.1002/hep.22428.
- Corpechot C, Carrat F, Poujol-Robert A, Gaouar F, Wendum D, Chazouilleres O, Poupon R. Noninvasive elastography-based assessment of liver fibrosis progression and prognosis in primary biliary cirrhosis. Hepatology. 2012 Jul;56(1):198-208. doi: 10.1002/hep.25599. Epub 2012 Jun 5.
- Honda A, Ikegami T, Nakamuta M, Miyazaki T, Iwamoto J, Hirayama T, Saito Y, Takikawa H, Imawari M, Matsuzaki Y. Anticholestatic effects of bezafibrate in patients with primary biliary cirrhosis treated with ursodeoxycholic acid. Hepatology. 2013 May;57(5):1931-41. doi: 10.1002/hep.26018. Epub 2013 Apr 5.
- Cuperus FJ, Halilbasic E, Trauner M. Fibrate treatment for primary biliary cirrhosis. Curr Opin Gastroenterol. 2014 May;30(3):279-86. doi: 10.1097/MOG.0000000000000056.
- Krupp LB, LaRocca NG, Muir-Nash J, Steinberg AD. The fatigue severity scale. Application to patients with multiple sclerosis and systemic lupus erythematosus. Arch Neurol. 1989 Oct;46(10):1121-3. doi: 10.1001/archneur.1989.00520460115022.
- Zuniga MA, Carrillo-Jimenez GT, Fos PJ, Gandek B, Medina-Moreno MR. [Evaluation of health status using Survey SF-36: preliminary results in Mexico]. Salud Publica Mex. 1999 Mar-Apr;41(2):110-8. Spanish.
- Duran-Arenas L, Gallegos-Carrillo K, Salinas-Escudero G, Martinez-Salgado H. [Towards a Mexican normative standard for measurement of the short format 36 health-related quality of life instrument]. Salud Publica Mex. 2004 Jul-Aug;46(4):306-15. doi: 10.1590/s0036-36342004000400005. Spanish.
- Rudic JS, Poropat G, Krstic MN, Bjelakovic G, Gluud C. Bezafibrate for primary biliary cirrhosis. Cochrane Database Syst Rev. 2012 Jan 18;1:CD009145. doi: 10.1002/14651858.CD009145.pub2.
Study record dates
Study Major Dates
Study Start
Primary Completion (Anticipated)
Study Completion (Anticipated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Digestive System Diseases
- Pathologic Processes
- Liver Diseases
- Biliary Tract Diseases
- Bile Duct Diseases
- Cholestasis, Intrahepatic
- Cholestasis
- Fibrosis
- Liver Cirrhosis
- Liver Cirrhosis, Biliary
- Molecular Mechanisms of Pharmacological Action
- Antimetabolites
- Gastrointestinal Agents
- Hypolipidemic Agents
- Lipid Regulating Agents
- Cholagogues and Choleretics
- Ursodeoxycholic Acid
- Bezafibrate
Other Study ID Numbers
- 1757
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
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