Randomized, double-blind, controlled study of glycerol phenylbutyrate in hepatic encephalopathy.
Hepatology. 2013 Jul 11;
Authors: Rockey DC, Vierling JM, Mantry P, Ghabril M, Brown RS, Alexeeva O, Zupanets IA, Grinevich V, Baranovsky A, Dudar L, Fadieienko G, Kharchenko N, Klaryts'ka I, Morozov V, Grewal P, McCashland T, Reddy KG, Reddy KR, Syplyviy V, Bass NM, Dickinson K, Norris C, Coakley D, Mokhtarani M, Scharschmidt BF, HALT-HE Study Group
Glycerol phenylbutyrate (GPB) lowers ammonia by providing an alternate pathway to urea for waste nitrogen excretion in the form of phenylacetylglutamine, which is excreted in urine. This randomized, double-blind, placebo-controlled phase 2 trial enrolled 178 patients with cirrhosis, including 59 already taking rifaximin, who had experienced two or more hepatic encephalopathy (HE) events in the prior 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, 6 mL orally twice daily, significantly reduced the proportion of patients who experienced an HE event (21% vs. 36%, p = 0.02), time to first event (hazard ratio (HR) = 0.56, p < 0.05) as well as total events (35 vs. 57, p = 0.04) and was associated with fewer HE hospitalizations (13 vs. 25, p = 0.06). Among patients not on rifaximin at enrollment, GPB reduced the proportion of patients with an HE event (10% vs. 32%, p < 0.01), time to first event (HR = 0.29, p value < 0.01 and total events (7 vs. 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). (Hepatology 2013;).
PMID: 23847109 [PubMed - as supplied by publisher]