Prolonged Follow-Up of Patients in the U.S. Multicenter Trial
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.

The impression that ursodeoxycholic acid (UDCA) prolongs survival in patients with primary biliary cirrhosis (PBC) is largely based on the data of Poupon and co-workers. In their 2-yr randomized, double-blind trial of UDCA versus placebo, the incidence of liver transplantation or death without transplantation was very low, and not different in the two treatment groups. At the end of this 2-yr period, patients originally on UDCA were continued on UDCA for 2 more yr, whereas the placebo group was now offered open-label UDCA, and most of this group took UDCA for the next 2 yr. During this latter 2-yr period of open-label UDCA, a striking increase was observed in the number of patients who underwent or were referred for liver transplantation in the treatment group that originally received placebo for 2 yr, then open-label UDCA for the next 2 yr compared to the group originally randomized to receive UDCA for 2 yr, and then received open-label UDCA for 2 additional yr. These observations, when combined with the experiences of the Mayo Clinic, and of the Canadian group that also compared UDCA to placebo led to the conclusion that UDCA prolongs survival in PBC patients, even though neither the Mayo Clinic trial nor the Canadian trial independently demonstrated a statistically significant effect of UDCA on survival. It was only when the results of these three independent trials were combined, that a positive UDCA effect was said to exist, and then much of the data were obtained from periods when UDCA and placebo were not compared simultaneously.

We, too, compared the effects of UDCA versus placebo in PBC patients randomized and treated in a 2-yr double-blind clinical trial. Although we, like almost all others who have assessed UDCA in PBC patients, found impressive effects of UDCA on improving markers of liver inflammation and cholestasis, and some aspects of liver histology, we did not observe any advantage of UDCA in preventing liver transplantation or death without liver transplantation during the 2 yr of our placebo-controlled trial.

At the completion of our placebo-controlled trial, all the patients were offered UDCA, and virtually all continued to take UDCA thereafter in the open-label phase of our study. The current report presents our observations on the incidence of liver transplantation or death without transplantation over the ensuing years in this study group. Our findings have been presented earlier in part in abstract form.