Randomized, double-blind, controlled study of glycerol phenylbutyrate in hepatic
encephalopathy.
Author(s): Rockey DC(1), Vierling JM, Mantry P, Ghabril M, Brown RS Jr, 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.
Collaborators: Ahmed A, Balart L, Berk B, Brown K, Frolov A, Howell C, Khrustalev
O, Lucey M, Maliakkal B, Mendoza A, O'Brien C, O'Shea R, Porayko M, Radchenko V,
Rahimi R, Shah N, Shetty K, Sigal S, Storozhakov G, Zucker S, Tobias H, Voigt M,
Weinman S, Wolf D, Zhidkov K, Zvyagintseva T.
Affiliation(s): Author information:
(1)Medical University of SC, Charleston, SC.
Publication date & source: 2014, Hepatology. , 59(3):1073-83
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).
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