Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT04514965 |
| Other study ID # |
PBC Beza AU |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
October 1, 2020 |
| Est. completion date |
September 2026 |
Study information
| Verified date |
August 2022 |
| Source |
University of Aarhus |
| Contact |
Henning Grønbæk, Prof, MD |
| Phone |
+45 21679281 |
| Email |
henngroe[@]rm.dk |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Up to 40% of patients with PBC have an inadequate response to standard treatment with UDCA,
hence bezafibrate, a PPAR-agonist is being introduced as add-on therapy in these patients.
sCD163, fibrosis markers and bile acid composition are of special interest in PBC. In this
study, the investigators will investigate how treatment with bezafibrate influence levels of
macrophage activation markers and fibrosis markers as well as bile acid composition in
patients offered bezafibrate as add-on therapy to UDCA.
Description:
Primary biliary cholangitis (PBC) is an autoimmune cholestatic liver disease characterized by
destruction of intrahepatic bile ducts and progression to liver fibrosis and cirrhosis. The
diagnosis of PBC is based on the presence of two of three major criteria; unexplained serum
alkaline phosphatase (ALP) >1.5 times upper normal limit for more than 24 weeks, presence of
anti-mitochondrial antibodies (AMA), and compatible liver histology.
Ursodeoxycholic acid (UDCA) is currently the only approved drug used to treat PBC and
patients treated with UDCA have improved survival. In Denmark all PBC patients are offered
UDCA treatment. However, up to 40% of PBC patients may be classified as insufficient
responders to UDCA treatment with male gender, low age, and low Vitamin D level at diagnosis
associated with insufficient response. More precise predictors of insufficient response to
UDCA treatment are important to find as insufficient responders have worse 10-year survival
probability than responders. The high proportion of insufficient responders has fuelled the
search for novel treatment options, including fibrates, budesonide, and obeticholic acid.
Despite response to UDCA treatment, liver transplantation remains the only cure for PBC and
patients with expected survival less than one year are potential candidates for liver
transplantation.
Bezafibrate Bezafibrate is a pan-peroxisome proliferator-activated receptor (PPAR) agonist.
For decades, bezafibrate has been prescribed for various indications including
hyperlipidemia. Thus, adverse effects are well described. Recently, a phase 3 trial showed
promising results as an add-on therapy to UDCA in reducing ALP in PBC patients, who had
insufficient response to UDCA alone. Hence, Danish hepatologists are starting to use
bezafibrate as second line, add-on, therapy in PBC patients.
Soluble CD163 and fibrosis markers In PBC, inflammation is attributed to an immune response
to mitochondrial autoantigens followed by development of anti-mitochondrial antibodies
(AMAs); and accompanied by inflammation of small bile ducts. The pathogenesis includes both
CD4 and CD8 cells, which in the presence of biliary cells expressing the 2-oxo-dehydrogenase
pathway (PDC-E2) activates macrophages via granulocyte macrophage colony-stimulating factor.
The activated macrophages, together with AMAs, produce a proinflammatory response with
subsequent liver inflammation and fibrosis. Thus, macrophages seem to be involved in PBC
disease severity and progression. The investigators recently showed that the macrophage
activation marker soluble (s)CD163 is associated with long-term prognosis in PBC patients.
Further, the investigators research group have shown increased levels of sCD163 in relation
to liver fibrosis/cirrhosis in patients with chronic viral hepatitis (HBV and HCV),
non-alcoholic fatty liver disease (NAFLD/NASH) and alcoholic liver disease (alcoholic
hepatitis and cirrhosis) and liver disease severity including risk of portal hypertension and
development of complications and mortality. Moreover, the investigators also demonstrated
sCD163 is associated with early and long-term prognosis of patients with cirrhosis and
acute-on-chronic liver failure.
Fibrosis is a hallmark of liver disease progression and extracellular matrix (ECM) turnover
is a prominent feature of chronic inflammatory liver diseases including PBC. ECM protein
degradation and formation generate fragments reflecting aspects of the tissue turnover
balance when quantified in the blood. PRO-C3 and PRO-C4 reflect type III and IV collagen
formation, whereas C3M and C4M are markers for degradation of type III and IV. The
investigators aim to investigate changes in these fibrosis markers before and after
bezafibrate treatment, to demonstrate if these novel finger print protein biomarkers may be
useful for treatment response in PBC patients.
Bile acids In PBC there is intrahepatic accumulation of potentially cytotoxic bile acids
resulting in liver damage. Further the composition of bile acids is changed, resulting in
changes of microbiota and in the integrity of the intestinal wall, potentially allowing an
increased flux of inflammatory metabolites to the liver. Exploration of potential changes in
bile acid profile caused by bezafibrate treatment may improve understanding of the treatment
effects and provide identification of specific treatment targets.
