Evaluation of Valproic Acid (VPA) as Adjunctive Therapy for Liver Transplant Patients With Moderate to Severe Hemorrhage at Risk of Ischemia Reperfusion (I/R) Injury

I/R injury remains a major clinical problem during liver transplantation. In addition to the implanted liver graft suffering from significant I/R injury due to the transplant process itself, other organs such as the kidneys frequently demonstrate significant I/R injury associated with substantial morbidity and mortality. Among liver transplant patients, especially those who have suffered significant blood loss and prolonged hypotension requiring multiple vasopressors, the rate of acute kidney injury (AKI) is reported to be >50%.

VPA is an anticonvulsant drug that was approved by the Food and Drug Administration (FDA) in 1978. VPA was developed for use as monotherapy or adjunctive therapy for the treatment of seizure disorders, mania associated with bipolar disorder, and migraine. Both oral and intravenous (IV) formulations are available. Doses up to 60 milligram (mg)/kilogram (kg)/day for up to 14 days have been demonstrated to be safe and effective. More recently, a study has shown that a single dose of intravenous VPA at up to 140 mg/kg is safe in healthy volunteers. VPA has been recognized as an HDAC inhibitor (HDACI) shown to reduce the inflammatory response and oxidative stress in septic mice, thereby protecting against renal injury. The molecular mechanisms conferring anticonvulsant properties associated with VPA have not been clearly elucidated to date but likely include increasing levels of γ-aminobutyric acid in the central nervous system (CNS), reduction in N-Methyl-D-Aspartate-mediated excitation, and blockade of voltage gated sodium and L-type calcium channels. More recently, VPA has shown HDACI potential, specifically targeting class I (subclasses Ia and Ib) and class II (subclass IIa) HDAC proteins. Given that VPA modulates multiple pathways involved in AKI, it theoretically could prevent kidney dysfunction and inflammation that is induced by I/R injury.

The aim of this study is to evaluate the effect of VPA on reducing I/R injury related to organ damage in the kidneys in liver transplant patients with moderate-to-severe hemorrhage. The primary objective is to evaluate the effect of VPA on reducing AKI compared with placebo in liver transplant patients with expected moderated-to-severe hemorrhage at risk for I/R injury. The two secondary objectives are: 1) To assess the perioperative pharmacokinetics (PK) of VPA in liver transplant patients with moderate-to-severe hemorrhage, and 2) To evaluate the safety of VPA administered as IV infusion in liver transplant patients with moderate-to-severe hemorrhage at risk of I/R injury.

This is a phase 2, single-dose, multicenter, double-blind, randomized, placebo-controlled study. Subjects will be randomized in a 1:1 ratio to receive a single dose of 140 mg/kg of VPA plus standard of care (SOC) or the placebo plus SOC, administered via IV infusion in the OR within 45 min after induction of anesthesia (administration of hypnotic). Clinical evaluations such as physical examination, vital signs, electrocardiogram, and laboratory results will be collected. AKI will be used to assess VPA efficacy. Myocardial injury and laboratory measurements (hematology, chemistry, coagulation profile, and urinalysis) will be used to monitor subject safety. Outcome measures including in-hospital mortality, length of intensive care unit (ICU) and/or stepdown unit (SDU) stay, length of hospital stay, number of alive and ventilator free days (aVFD), and incidence of renal replacement therapy (RRT) will also be collected. Blood samples will be collected for PK analysis. The PK analysis will correlate study drug exposures with safety profiles. Specimens (plasma, peripheral blood mononuclear cells (PBMCs), and urine) will be stored for future undetermined study-related analyses, including pharmacodynamics (PD) and VPA responsiveness studies. These studies may correlate PK profiles to molecular changes related to beneficial properties of VPA.

Male and non-pregnant, non-breastfeeding female liver transplant patients between 18 and 80 years old will be recruited for the study. Patients will be those scheduled to undergo liver transplant surgery and expected to require transfusion of 3 or more units of red cell product. Only patients who can provide consent or for whom a Legally Authorized Representative (LAR) can provide consent, will be enrolled. Approximately 50 subjects will be recruited from across four major medical centers for participation in this study.