Prolonged follow-up of patients in the U.S. multicenter trial of ursodeoxycholic acid for primary biliary cirrhosis

Abstract

Objective: Randomized, double-blind, placebo-controlled trials of ursodeoxycholic acid (UDCA) in patients with primary biliary cirrhosis (PBC) have not demonstrated improvement in survival during the placebo-controlled phases of these trials. Analyses purporting to demonstrate a survival advantage of UDCA are largely dependent on data obtained after the placebo phases were terminated, and placebo-treated patients were offered open-label UDCA. After completion of our 2-yr placebo-controlled trial of UDCA in which we observed no survival benefit for UDCA, we provided the patients with open-label UDCA to see if delay in providing UDCA for 2 yr had any effect on subsequent liver transplantation or death without liver transplantation.

Methods: In our previously reported 2-yr placebo-controlled trial, 151 patients with PBC were randomized to receive either UDCA (n = 77) or placebo (n = 74). The number of patients who progressed to liver transplantation or death without transplantation were similar in both the groups, 12 (16%) in the UDCA-treated and 11 (15%) in placebo-treated patients. All the patients were then offered open-label UDCA, with 61 original UDCA and 56 original placebo-treated patients now taking UDCA in an extended open-label phase of the trial.

Results: No significant differences were observed in the number of patients who underwent liver transplantation or died without liver transplantation in the open-label phase of the trial. Moreover, no difference in the time to these endpoints was seen over the period of observation of as long as 6 yr from the time of initial randomization.

Conclusions: Results of open-label extensions of previous conducted placebo-controlled trials of UDCA in PBC leave uncertain whether UDCA impacts significantly on liver transplantation and death without liver transplantation in patients with PBC.

Figure 1

Kaplan–Meier assessment of survival using time from randomization to liver transplantation or death without transplantation. There were 26 observed events in the treatment group originally randomized to placebo (n = 74), then after 2 yr continued on open-label UDCA therapy. The expected number of events in this group was 24.6. Twenty-four events were observed in the group originally randomized to UDCA (n = 77) and continued on UDCA thereafter. Expected events in this latter group were 25.4. χ² = 0.2 on one degree of freedom, p = 0.688.

Figure 2

Comparison of results of UDCA as percent of bile acids in fasting bile obtained at 2 yr in the placebo-controlled trials of Combes et al. (6) and Lindor et al. (3). The figure represents a composite of Figure 5 previously published in Reference (6), and Figure 6 published in Reference (3). Permission was obtained from the copyright owners, i.e., the American Association for the Study of Liver Diseases and the American Gastroenterological Association, to reproduce this material. Administered doses of UDCA were 10–12 mg/kg/day (6) and 13–15 mg/kg/day (3) in these respective trials. Mean percent ± SD was 37.0 ± 16.3 for patients in stratum 1; 42.1 ± 17.4 for stratum 2; and 42.7 ± 12.9 for strata 3 and 4 (6). The mean UDCA value for the Mayo Clinic trial was 39.5% ((3), data shown on right-hand side of Figure 2.)