Randomized, double-blind, controlled study of glycerol phenylbutyrate in hepatic encephalopathy

Abstract

Glycerol phenylbutyrate (GPB) lowers ammonia by providing an alternate pathway to urea for waste nitrogen excretion in the form of phenylacetyl glutamine, which is excreted in urine. This randomized, double-blind, placebo-controlled phase II trial enrolled 178 patients with cirrhosis, including 59 already taking rifaximin, who had experienced two or more hepatic encephalopathy (HE) events in the previous 6 months. The primary endpoint was the proportion of patients with HE events. Other endpoints included the time to first event, total number of events, HE hospitalizations, symptomatic days, and safety. GPB, at 6 mL orally twice-daily, significantly reduced the proportion of patients who experienced an HE event (21% versus 36%; P=0.02), time to first event (hazard ratio [HR]=0.56; P<0.05), as well as total events (35 versus 57; P=0.04), and was associated with fewer HE hospitalizations (13 versus 25; P=0.06). Among patients not on rifaximin at enrollment, GPB reduced the proportion of patients with an HE event (10% versus 32%; P<0.01), time to first event (HR=0.29; P<0.01), and total events (7 versus 31; P<0.01). Plasma ammonia was significantly lower in patients on GPB and correlated with HE events when measured either at baseline or during the study. A similar proportion of patients in the GPB (79%) and placebo groups (76%) experienced adverse events.

Conclusion: GPB reduced HE events as well as ammonia in patients with cirrhosis and HE and its safety profile was similar to placebo. The findings implicate ammonia in the pathogenesis of HE and suggest that GPB has therapeutic potential in this population. (Clinicaltrials.gov, NCT00999167).

Figure 1

Disposition of patients. The flow chart indicates the disposition of the 276 patients screened, including the most common reasons for screen failure and the most common reasons for discontinuation among the 178 patients enrolled.

Figure 2

Time to HE event. The time to the first HE event over time is depicted for all patients (top panel; n = 178), in patients not on rifaximin at baseline (middle panel; n = 119), and in patients on rifaximin at baseline (bottom panel; n = 59).

Figure 3

Cumulative HE events. Cumulative HE events over time are shown for all patients (n = 178), patients not on rifaximin at baseline (middle panel; n = 119), and for patients on rifaximin either at baseline or who were put on rifaximin during the study (bottom panel; n = 69). The bottom panel includes 9 patients not on rifaximin at study entry randomized to placebo who began rifaximin treatment after an on-study HE event and 1 patient randomized to GPB who received rifaximin after the last dose of GPB.

Figure 4

Baseline ammonia in relation to HE events. The relationship between baseline ammonia and HE events that occurred on study (mean [+], median [horizontal line], 25%-75% [box] and 5%-95% [whiskers]) is shown.