Study terminated by the Sponsor

The purpose of this study is to find out if a drug called valproic acid (VPA) will protect organs (like the kidneys) from harmful effects caused by the temporary drop and then rise of blood flow and oxygen (called ischemia reperfusion (I/R) injury that sometimes happens during liver transplant surgery. VPA is an approved drug for treating conditions such as seizures and migraines for many years. However, it is not approved for use at the higher dose that will be used in this study or for protecting organs from I/R injury. This study will enroll liver transplant patients and randomly assign them to receive either VPA diluted in salt water or salt water without VPA (placebo) and then follow the patients and compare their organ function and overall outcome. This study is masked meaning that the patients, doctors, and nurses will not know which patient received which treatment. The study treatment will be given in addition to the care that liver transplant patients normally receive. The researchers doing this study believe that VPA will lessen organ injury caused by I/R, meaning that patients who receive VPA will experience less kidney injury when compared to patients who receive the placebo.

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.

Based on the available safety profile data from multi-dose clinical trials of VPA, the product safety information sheet, as well as the VPA Phase 1 study which evaluated the safety of single ascending doses of VPA, it has been determined that a dose of 140 mg/kg is safe and well-tolerated with minimal adverse reactions. However, given that patients studied at the 140 mg/kg dose in the phase 1 study were relatively healthy compared to the proposed patient population in this study and unanticipated Adverse Events (AEs) may occur, the study team will monitor all study subjects closely for AEs throughout the study. All AEs will be evaluated for duration, seriousness, severity, and relationship to the study drug, and reported accordingly.

This study will be monitored according to the data and safety monitoring plan which will outline the different levels of monitoring and the responsible parties. A Safety Review Committee (SRC) will review and monitor all safety information and compliance data as well as the overall study progress on a regular basis. A Medical Monitor (MM) with relevant clinical and research expertise will oversee the clinical study and provide ongoing medical monitoring. The clinical site Principal Investigators (PIs) will be responsible for ensuring that all AEs that occur in subjects during the AE reporting period are managed and reported in accordance with the protocol, Sponsor requirements, and any applicable regulations and institutional policies. A Data Monitoring Committee (DMC) will monitor implementation and progress of the study and review the accumulating endpoint and safety data by treatment arm to detect evidence of early significant benefit or harm for subjects while the study is in progress.

As the main purpose of this study is to evaluate safety of VPA in the study population and to investigate efficacy signal, this is a proof-of-concept (PoC) study. Because it is a PoC study rather than a confirmatory one, it has been assumed that a total sample size of 50 subjects (25 in each treatment arm) will be sufficient to provide adequate clinical evidence of safety and potential efficacy, and to support decision-making on whether a larger pivotal confirmatory Phase 3 study would be justified.

A statistical analysis plan (SAP) that details the analytical principles and statistical techniques to be employed in order to address the primary and secondary objectives will be developed. Demographic and relevant baseline characteristics will be presented and summarized descriptively by treatment for the randomized, modified intent-to-treat (mITT), and per-protocol (PP) populations. The primary endpoint of KDIGO stages will be measured in ordinal scale as 0, 1, 2, or 3, where 0 indicates normal renal function and the progressively higher values indicate worsening renal function. The ordinal scale measurements will be analyzed using the proportional odds ordinal logistic regression model. The KDIGO stages will be the dependent variable and drug treatment will be used as the independent variable. The common odds ratio across the KDIGO stages and its 95% confidence interval will be calculated. Binary endpoints (e.g., incidence of AKI) will be analyzed by Fisher's exact test or logistic regression with treatment as an independent variable. The odds ratio and its 95% confidence interval will be calculated. Continuous outcomes will be analyzed by missed effects models with treatment and baseline value of the outcome (if applicable) as independent variables. Un-ordered categorical variables with more than two levels of outcome will be analyzed by a chi-square test. Ordered categorical variables with more than two levels of outcome will be analyzed in the same way as for the primary endpoint. Safety endpoints will be analyzed and summarized descriptively. Categorical variables will be summarized by count and percentage. Odds ratios and relative risks may be calculated to compare study drug with placebo in incidence of certain safety events. Continuous variables will be summarized by mean, SD, median, minimum, and maximum. Shift tables may be used to describe changes in certain laboratory values. The plan for the PK analysis is two-fold. First, a standard noncompartmental analysis will be performed to obtain descriptors of VPA exposure to explore potential relationships to the primary outcome), secondary outcomes, or any observed adverse effects. A population PK analysis will be performed to examine and, perhaps, explain the anticipated differing PK of VPA in the trial. Specifically, low protein binding of VPA and massive blood loss are expected to affect the elimination clearance and, perhaps, the volume of distribution of VPA. Characterizing the degree to which the PK are perturbed as well as the parameter variability in this population will be important for analyzing the relationship of VPA exposure to primary and secondary outcomes and determining the effects, if any, of factors related to disease or perioperative conditions to the PK of VPA.

No interim analyses will be performed for this study. This study does not have a formal stopping rule based on statistical testing. See Section 3.9 for more information on stopping rules. Missing data can occur in clinical studies, and they may have an impact on the results of statistical analyses. Every effort will be made to ensure that the amount of missing data is kept at a minimum.

Inclusion Criteria:

• Is aged 18 to 80 years old;
• Is male or non-pregnant, non-breastfeeding female;
• Is able to provide written informed consent or has an LAR from whom consent can be obtained;
• Body mass index (BMI) is between 18 kg/m2 and 35 kg/m2;
• Expected transfusion of 3 or more units of red cell product, as determined by the patient's provider; and
• Is scheduled to undergo liver transplant surgery without hepatocellular carcinoma (HCC) exception points.

Exclusion Criteria:

• Has a known history of adverse reaction to VPA;
• Is currently receiving VPA;
• Is pregnant or breastfeeding;
• Is in need of a simultaneous kidney transplant, or currently on RRT for either AKI or hepato-renal syndrome, type I (HRS-I);
• Is currently incarcerated or pending incarceration;
• Is known to have mitochondrial disorders caused by polymerase γ (POLG) mutations;
• Has acute liver failure;
• Has porto-pulmonary hypertension;
• Has hepato-pulmonary syndrome;
• Transplant procedure is a veno-venous bypass procedure;
• Is a living-donor transplant or a split liver transplant;
• Is scheduled to undergo liver transplant surgery with HCC exception points; or
• Has other unspecified reason/condition that, in the opinion of the clinical site PI, make the patient unsuitable for enrollment.

In addition to the individuals listed above, Sponsor's representatives such as clinical research associates who will perform site monitoring, the pharmacovigilance medical monitor, and all staff at the research sites other than the pharmacist of record will be masked.