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Phase 3 Study of Bezafibrate in Combination With Ursodeoxycholic Acid in Primary Biliary Cirrhosis (BEZURSO)

Primary Purpose

PBC

Status

Completed

Phase

Phase 3

Locations

France

Study Type

Interventional

Intervention

Bezafibrate

placebo

About this trial

This is an interventional treatment trial for PBC focused on measuring PBC, Bezafibrate

Eligibility Criteria

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

Inclusion Criteria:

Age > 18
Patient with PBC defined by 2 in 3 of the following criteria Positive antimitochondrial antibody type M2. Abnormal serum alkaline phosphatases (ALP > 1,5N) and aminotransferase (AST or ALT > 1N) activities.

Histological hepatic injuries consistent with PBC from biopsy specimens of at least 10 mm.

Patient treated with UDCA at the dose of 13 to 15 mg/kg/d (consistent to the AMM)
Patients showing an incomplete biochemical response to UDCA as defined by : ALP > 1,5N or AST > 1,5N or total bilirubin >17 µmol/l (with conjugated bilirubin > 8 µmol/l) after ≥ 3 months of UDCA at the dose of 13 - 15 mg/kg/day.

Exclusion Criteria:

Unsigned consent.
Patient with no social insurance or having medical assistant of state
Ascites or gastrointestinal bleeding (or history of these)
Serum total bilirubinemia > 50 μmols/L (3 mg/dl) (sample < 3 months)
Serum albuminemia < 35 g/l (sample < 3 months)
Prothrombin index < 70% (sample < 3 months)
Platelet count < 100000/mm3 (sample < 3 months)
Treatment with corticosteroids, immunosuppressive agents, fibrates (or other PPAR-agonists) or statin in the last 3 months
Any comorbidity susceptible to cause a hepatic impairment (HBV, HCV, or HIV seropositivity; excessive alcohol consumption; hemochromatosis, Wilson's disease, α1 antitrypsin deficiency; celiac disease; uncontrolled dysthyroidism; autoimmune hepatitis, inflammatory colitis)
Any severe comorbidity decreasing life expectancy
Intolerance or hypersensitivity to fibrates, to one of these components or other fibrates in general
Known photosensitivity reaction to fibrates
Pregnancy or desire of pregnancy
Breast-feeding
Renal failure (clearance of creatinine < 60 ml/mn)
Patient with congenital galactosemia, syndrome of glucose malabsorption, lactase deficiency due to the presence of lactose in tablets of bezafibrate 400 mg

Sites / Locations

Hepatology department - Hopital Saint Antoine

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Bezafibrate

Placebo

Arm Description

400 mg/Day

1 tablet/ day

Outcomes

Primary Outcome Measures

Percentage of patients with complete biochemical response.

The normalisation of hepatic biochemical tests (aminotransferases (AST, ALT), Alkaline Phosphatase, blood Albumin, blood bilirubin and prothrombin index).

Secondary Outcome Measures

Percentage of patients having biological or clinical adverse reaction.

Increase of ALT, AST or CPK > 5N

Percentage of patients having complete biochemical response.

Percentage of patients having complete biochemical response at Month 12.

Evolution of the pruritus.

Pruritus is measured via visual analogical scale every 3 months from month 0 to month 24

Assessment of the fatigue and the quality of life.

Measured via French questionnaire version of NHP (Nottingham Health Profile) every 12 months from month 0 to month 24

Evolution of liver fibrosis surrogate markers.

assessment of hyaluronic acid serum concentration and hepatic transient elastography (Fibroscan®)

Evolution of the portal hypertension markers.

Occurrence of ascites, decrease in the platelet count below 150000/mm3 or of more than 30% of its initial value, evolution of the ultrasound data of the splanchnic circulation, occurrence or size progression of oesophageal varices (endoscopy)

Histological evolution: Histopathological examination of biological sample before enrolment and at the end of the study.

Quantification of the fibrosis and the inflammatory and destructive injuries.

Evolution of the biological markers of the hepatic function or being in the usual prognostic scores (Mayo, Child, MELD).

Blood albumin, prothrombin time, INR, blood bilirubin, creatinine blood level.

Survival without transplantation and hepatic impairment.

Occurrence of ascites, a digestive variceal bleeding, a hepatic encephalopathy, or a doubling of the total blood bilirubin exceeding the threshold of 50 µmols/L (3 mg/dl).

Full Information

NCT ID

NCT01654731

First Posted

July 30, 2012

Last Updated

February 23, 2023

Sponsor

Assistance Publique - Hôpitaux de Paris

1. Study Identification

Unique Protocol Identification Number

NCT01654731

Brief Title

Phase 3 Study of Bezafibrate in Combination With Ursodeoxycholic Acid in Primary Biliary Cirrhosis

Acronym

BEZURSO

Official Title

Multicenter, Randomized, Double-blind Placebo Controlled Trial of Bezafibrate for the Treatment of Primary Biliary Cirrhosis in Patients With Incomplete Response to Ursodesoxycholic Acid Therapy.

Study Type

Interventional

2. Study Status

Record Verification Date

February 2023

Overall Recruitment Status

Completed

Study Start Date

October 15, 2012 (Actual)

Primary Completion Date

December 31, 2016 (Actual)

Study Completion Date

December 31, 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Assistance Publique - Hôpitaux de Paris

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease that eventually leads to end-stage liver failure and death unless liver transplantation (LT) is performed. Ursodeoxycholic acid (UDCA) administered orally at the daily dose of 13-15 mg/kg is currently the only drug approved for the treatment of PBC. UDCA consistently improves biochemical liver tests, prolongs survival without LT, and delays histological progression as well as the occurrence of portal hypertension. However, a significant proportion (40%) of patients treated with UDCA shows an incomplete biochemical response and remains at high risk of death or LT. The development of new treatments in combination with UDCA is therefore needed. Several candidates exist among which is Bezafibrate. Bezafibrate belongs to the fibrates' pharmacological class, which has been developed 4 decades ago for the treatment of mixed hyperlipidaemia. Bezafibrate is cheap, widely available and well tolerated. There is now a substantial body of circumstantial evidence supporting that fibrates, and Bezafibrate in particular, are well tolerated and can improve biochemical liver tests in patients with PBC with incomplete response to UDCA. However, despite several positive successful pilot studies, there are still no phase 3 randomized placebo-controlled trials of fibrates for the treatment of PBC. The purpose of this protocol is therefore to conduct such a trial in a selected population of patients with PBC based on an incomplete biochemical response after 6 months of UDCA therapy.

Detailed Description

This is a multi-center, randomized (treatment will be assigned by chance), placebo-controlled (an inactive substance will be compared with the test drug to see whether the drug has a real effect), parallel-group (two or more groups of patients will receive different treatments) study that will assess the efficacy and safety of bezafibrate in patients with primary biliary cirrhosis (PBC) who had an inadequate biochemical response to ursodeoxycholic acid, as defined by the Paris II criteria. Bezafibrate 400 mg or placebo will be daily administered in combination with ursodeoxycholic acid (UDCA) 13-15 mg/kg/d for 24 months. Patient safety will be monitored. Primary end-point will be the percentage of patients with a complete normalization of the following biochemical tests: alkaline phosphatase, aminotransferases, total bilirubin, serum albumin, and prothrombin index. Secondary endpoints will include the percentage of drug-related adverse events, survival rates without liver transplantation or liver decompensation, time course of non-invasive liver fibrosis measurements (Fibroscan, serum hyaluronic acid), time course of liver histological parameters (fibrosis stage, necro-inflammatory grade, ductopenia) assessed on percutaneous biopsy specimens, time course of endoscopic, ultrasound, and biochemical features of portal hypertension, time course of pruritus and of quality of life using validated scales.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

PBC

Keywords

PBC, Bezafibrate

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

100 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Bezafibrate

Arm Type

Experimental

Arm Description

400 mg/Day

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

1 tablet/ day

Intervention Type

Drug

Intervention Name(s)

Bezafibrate

Intervention Type

Drug

Intervention Name(s)

placebo

Primary Outcome Measure Information:

Title

Percentage of patients with complete biochemical response.

Description

The normalisation of hepatic biochemical tests (aminotransferases (AST, ALT), Alkaline Phosphatase, blood Albumin, blood bilirubin and prothrombin index).

Time Frame

24 months

Secondary Outcome Measure Information:

Title

Percentage of patients having biological or clinical adverse reaction.

Description

Increase of ALT, AST or CPK > 5N

Time Frame

24 months

Title

Percentage of patients having complete biochemical response.

Description

Percentage of patients having complete biochemical response at Month 12.

Time Frame

12 months

Title

Evolution of the pruritus.

Description

Pruritus is measured via visual analogical scale every 3 months from month 0 to month 24

Time Frame

24 months

Title

Assessment of the fatigue and the quality of life.

Description

Measured via French questionnaire version of NHP (Nottingham Health Profile) every 12 months from month 0 to month 24

Time Frame

24 months

Title

Evolution of liver fibrosis surrogate markers.

Description

assessment of hyaluronic acid serum concentration and hepatic transient elastography (Fibroscan®)

Time Frame

24 months

Title

Evolution of the portal hypertension markers.

Description

Time Frame

24 months

Title

Histological evolution: Histopathological examination of biological sample before enrolment and at the end of the study.

Description

Quantification of the fibrosis and the inflammatory and destructive injuries.

Time Frame

24 months

Title

Evolution of the biological markers of the hepatic function or being in the usual prognostic scores (Mayo, Child, MELD).

Description

Blood albumin, prothrombin time, INR, blood bilirubin, creatinine blood level.

Time Frame

24 months

Title

Survival without transplantation and hepatic impairment.

Description

Occurrence of ascites, a digestive variceal bleeding, a hepatic encephalopathy, or a doubling of the total blood bilirubin exceeding the threshold of 50 µmols/L (3 mg/dl).

Time Frame

24 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Age > 18 Patient with PBC defined by 2 in 3 of the following criteria Positive antimitochondrial antibody type M2. Abnormal serum alkaline phosphatases (ALP > 1,5N) and aminotransferase (AST or ALT > 1N) activities. Histological hepatic injuries consistent with PBC from biopsy specimens of at least 10 mm. Patient treated with UDCA at the dose of 13 to 15 mg/kg/d (consistent to the AMM) Patients showing an incomplete biochemical response to UDCA as defined by : ALP > 1,5N or AST > 1,5N or total bilirubin >17 µmol/l (with conjugated bilirubin > 8 µmol/l) after ≥ 3 months of UDCA at the dose of 13 - 15 mg/kg/day. Exclusion Criteria: Unsigned consent. Patient with no social insurance or having medical assistant of state Ascites or gastrointestinal bleeding (or history of these) Serum total bilirubinemia > 50 μmols/L (3 mg/dl) (sample < 3 months) Serum albuminemia < 35 g/l (sample < 3 months) Prothrombin index < 70% (sample < 3 months) Platelet count < 100000/mm3 (sample < 3 months) Treatment with corticosteroids, immunosuppressive agents, fibrates (or other PPAR-agonists) or statin in the last 3 months Any comorbidity susceptible to cause a hepatic impairment (HBV, HCV, or HIV seropositivity; excessive alcohol consumption; hemochromatosis, Wilson's disease, α1 antitrypsin deficiency; celiac disease; uncontrolled dysthyroidism; autoimmune hepatitis, inflammatory colitis) Any severe comorbidity decreasing life expectancy Intolerance or hypersensitivity to fibrates, to one of these components or other fibrates in general Known photosensitivity reaction to fibrates Pregnancy or desire of pregnancy Breast-feeding Renal failure (clearance of creatinine < 60 ml/mn) Patient with congenital galactosemia, syndrome of glucose malabsorption, lactase deficiency due to the presence of lactose in tablets of bezafibrate 400 mg

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Christophe Corpechot, Doctor

Organizational Affiliation

Assistance Publique

Official's Role

Principal Investigator

Facility Information:

Facility Name

Hepatology department - Hopital Saint Antoine

City

Paris

ZIP/Postal Code

75012

Country

France

12. IPD Sharing Statement

Citations:

PubMed Identifier

29874528

Citation

Corpechot C, Chazouilleres O, Rousseau A, Le Gruyer A, Habersetzer F, Mathurin P, Goria O, Potier P, Minello A, Silvain C, Abergel A, Debette-Gratien M, Larrey D, Roux O, Bronowicki JP, Boursier J, de Ledinghen V, Heurgue-Berlot A, Nguyen-Khac E, Zoulim F, Ollivier-Hourmand I, Zarski JP, Nkontchou G, Lemoinne S, Humbert L, Rainteau D, Lefevre G, de Chaisemartin L, Chollet-Martin S, Gaouar F, Admane FH, Simon T, Poupon R. A Placebo-Controlled Trial of Bezafibrate in Primary Biliary Cholangitis. N Engl J Med. 2018 Jun 7;378(23):2171-2181. doi: 10.1056/NEJMoa1714519.

Results Reference

background

PubMed Identifier

30589964

Citation

Corpechot C, Chazouilleres O, Lemoinne S, Rousseau A. Letter: reduction in projected mortality or need for liver transplantation associated with bezafibrate add-on in primary biliary cholangitis with incomplete UDCA response. Aliment Pharmacol Ther. 2019 Jan;49(2):236-238. doi: 10.1111/apt.15049. No abstract available.

Results Reference

derived

Links:

URL

https://pubmed.ncbi.nlm.nih.gov/29874528/

Description

Results

Learn more about this trial

Phase 3 Study of Bezafibrate in Combination With Ursodeoxycholic Acid in Primary Biliary Cirrhosis

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