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

NCT02937012 | Unknown Phase 3 DMC

• 1 other identifier: 1757
• Study Type: interventional
• Target: 34
• Locations: 1 country
• Sites: 1

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?

Conditions

Primary Biliary Cirrhosis

Keywords

Primary Biliary Cirrhosis; Primary Biliary Cholangitis; Bezafibrate; Ursodeoxycholic acid

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (1)

• Increase in liver transaminases or development of rhabdomyolysis

  Follow-up every 3 months for 12 months.

Other Outcomes (6)

• Comparison of fatigue between groups

  Two evaluations: At enrollment and 12 months later.

• Quality of life

  Two evaluations: At enrollment and 12 months later.

• Pruritus intensity

  Follow-up every 3 months for 12 months.

Study Arms (2)

Bezafibrate & Ursodeoxycholic acid

EXPERIMENTAL

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; Drug: Ursodeoxycholic Acid

Placebo & Ursodeoxycholic acid

PLACEBO COMPARATOR

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; Drug: Placebo (for Bezafibrate)

Interventions

Bezafibrate DRUG

Bezafibrate 200 mg manufactured in a pill/capsule presentation

Also known as: Bezalip

Bezafibrate & Ursodeoxycholic acid

Ursodeoxycholic Acid DRUG

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

Also known as: Ursofalk

Bezafibrate & Ursodeoxycholic acid; Placebo & Ursodeoxycholic acid

Placebo (for Bezafibrate) DRUG

Starch pill/capsule manufactured to mimic bezafibrate 200 mg tablet

Also known as: Does not apply

Placebo & Ursodeoxycholic acid

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran: lead

Study Sites (1)

Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran

Mexico City, 14000, Mexico

RECRUITING

Related Publications (23)

• Flores A, Mayo MJ. Primary biliary cirrhosis in 2014. Curr Opin Gastroenterol. 2014 May;30(3):245-52. doi: 10.1097/MOG.0000000000000058.

  PMID: 24671010 RESULT

• 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.

  PMID: 19554543 RESULT

• 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.

  PMID: 15128074 RESULT

• 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.

  PMID: 22245904 RESULT

• 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.

  PMID: 16299032 RESULT

• 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.

  PMID: 17399846 RESULT

• 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.

  PMID: 15017671 RESULT

• 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.

  PMID: 12360466 RESULT

• 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.

  PMID: 9934730 RESULT

• 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.

  PMID: 16863557 RESULT

• 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.

  PMID: 10347106 RESULT

• 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.

  PMID: 16848809 RESULT

• 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.

  PMID: 16530513 RESULT

• 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.

  PMID: 10051462 RESULT

• 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.

  PMID: 23141888 RESULT

• 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.

  PMID: 18752324 RESULT

• 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.

  PMID: 22271046 RESULT

• 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.

  PMID: 22911624 RESULT

• 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.

  PMID: 24625898 RESULT

• 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.

  PMID: 2803071 RESULT

• 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.

  PMID: 10343514 RESULT

• 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.

  PMID: 15468571 RESULT

• Rudic JS, Poropat G, Krstic MN, Bjelakovic G, Gluud C. Bezafibrate for primary biliary cirrhosis. Cochrane Database Syst Rev. 2012 Jan 18;1(1):CD009145. doi: 10.1002/14651858.CD009145.pub2.

  PMID: 22259000 RESULT

Related Links

• 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

MeSH Terms

Conditions

Liver Cirrhosis, Biliary

Interventions

Bezafibrate; Ursodeoxycholic Acid

Condition Hierarchy (Ancestors)

Cholestasis, Intrahepatic; Cholestasis; Bile Duct Diseases; Biliary Tract Diseases; Digestive System Diseases; Liver Diseases; Liver Cirrhosis; Fibrosis; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Benzamides; Amides; Organic Chemicals; Fibric Acids; Isobutyrates; Butyrates; Acids, Acyclic; Carboxylic Acids; Benzoates; Acids, Carbocyclic; Chlorobenzoates; Phenyl Ethers; Ethers; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Phenols; Deoxycholic Acid; Cholic Acids; Bile Acids and Salts; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Cholanes

Study Officials

• Edgardo Eric Lopez Mendez, MD

  Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Edgardo Eric Lopez Mendez, MD

CONTACT

(52)(55)54870900; ericlopezmendez@yahoo.com.mx

Sergio Gabriel Munoz Martinez, MD

CONTACT

(52)(55)54870900; sergio_sg@hotmail.com

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Hepatologist

Study Record Dates

• First Submitted: October 13, 2016
• First Posted: October 18, 2016
• Study Start: October 1, 2016
• Primary Completion: April 1, 2019
• Study Completion: December 1, 2019
• Last Updated: April 23, 2018

Record last verified: 2018-04

Locations

ME (1)