A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL OF URSODEOXYCHOLIC ACID IN PRIMARY BILIARY-CIRRHOSIS

One hundred fifty one patients with primary biliary cirrhosis (PBC) gr ouped into four strata based on entry serum bilirubin (<2 mg/dL vs, 2 mg/dL or greater) and liver histology (stages I, II vs, stages III, IV -Ludwig criteria) were randomized within each stratum to ursodiol- or placebo given in a single dose of 10 to 12 mg/kg at bedtime for 2 year s. Placebo- (n = 74) and ursodiol-treated (n = 77) patients were well matched at baseline for demographic and prognostic factors. Ursodiol i nduced major improvements in biochemical tests of the liver in strata 1 and 2 (entry bilirubin <2), but had less effect on laboratory tests in patients with entry serum bilirubin of greater than or equal to 2 ( strata 3 and 4). Histology was favorably affected by ursodiol in patie nts in strata 1 and 2 but not in strata 3 and 4. Ursodiol enrichment i n fasting bile obtained at the conclusion of the trial was approximate ly 40% and comparable in all strata. Thus, differences in ursodiol enr ichment of the bile acid pool do not explain better responses of labor atory tests and histology found in patients with less advanced PBC. Pa tients treated with ursodiol tended to develop a treatment failure les s frequently than those who received placebo, particularly in strata 1 and 2 (ursodiol 42%, placebo 60%, P =.078). Development of severe sym ptoms (fatigue/pruritus) and doubling of serum bilirubin were reduced significantly in ursodiol-treated patients. Major complications of liv er disease, progression to liver transplantation or death, occurred in 10.5% and 76.6%, respectively, in patients who had an entry serum bil irubin of <2 or greater than or equal to 2 mg/dL. The incidence of the se complications was comparable in ursodiol- and placebo-treated patie nts. Treatment failure occurred sooner in placebo than in ursodiol-tre ated patients in strata 1 and 2 but at the same rate in similarly trea ted patients in strata 3 and 4. Patients with advanced disease are unl ikely to benefit from ursodiol. Trials longer than 2 years will likely be needed to determine whether ursodiol reduces major complications o f liver disease in patients with milder disease.