Ursodiol-Methotrexate for Primary Biliary Cirrhosis
Condition: Liver Cirrhosis, Biliary
MeSH terms: Liver Cirrhosis; Liver Cirrhosis, Biliary; Fibrosis
Study type: Interventional
Phase: Phase 3

Summary: 
      The major thrust is to determine whether treatment of patients with Primary Biliary Cirrhosis
      (PBC) with Ursodiol (Ursodeoxycholic Acid-UDCA) plus methotrexate (MTX) is more effective
      than treatment with UDCA alone.
    

Detailed description: 
      PBC is a chronic cholestatic liver disease, predominantly of women, in which interlobular and
      septal bile ducts undergo inflammation and destruction. Once initiated, the disease persists
      and progresses at varying rates. Neither the initiating nor perpetuating mechanisms are well
      understood. Current concepts of pathogenesis include (1) destruction of bile ducts is
      maintained and perhaps initiated by autoimmune mechanisms; (2) hydrophobic bile acids which
      accumulate in serum and liver cause functional and cytotoxic liver injury; (3) cytokines and
      lymphokines released at sites of inflammation may contribute to cell damage and fibrosis. A
      considerable body of evidence indicates that UDCA when fed orally leads to improvement in
      liver tests, in pruritus and in liver histology. There exist differences in opinion as to
      whether development of complications of liver disease, liver transplantation or
      transplant-free survival is affected. UDCA, a relatively non-toxic bile acid, when
      administered orally, alters the composition of the bile acid pool in factor of its enrichment
      with UDCA and appears to protect against the cytotoxic effects of endogenous bile acids that
      accumulate as a result of bile acid destruction. MTX is being shown to improve liver tests,
      symptoms and liver histology in a small number of precirrhotic patients with PBC. The
      mechanism of action is unknown but felt to be related to anti-inflammatory immunosuppressive
      effects of MTX. The current trial explores whether MTX improves the therapeutic effects of
      UDCA in PBC. Patients with PBC whose serum bilirubin is less than 3 mg%, who have been on
      UDCA for at least 6 months, and who satisfy a series of inclusion and exclusion criteria are
      stratified into 2 groups on the basis of liver histologic stage (Ludwig classification),
      i.e., early (Stages I and II) versus late (Stages III or IV). They are then randomized to
      receive either methotrexate or its placebo as a second drug while continuing to receive UDCA.
      The relative value of the two treatment arms is assessed by comparing their effects on
      symptoms, results of laboratory tests, development of complications of liver disease,
      histologic changes in liver, liver transplantation, and on transplant-free survival. The
      safety of each therapeutic regimen is also being determined.
    

Intervention name(s): Methotrexate
Intervention type(s): Drug
Intervention MeSH terms: Methotrexate
Allocation: Randomized
Masking: Double
Primary purpose: Treatment
Keywords: primary biliary cirrhosis; Ursodeoxycholic acid; UDCA; MTX; Hepatology; methotrexate; liver