Valproic Acid (VPA) for Acute Kidney Injury (AKI) in Liver Transplant Patients

NCT04531592 | Withdrawn Phase 2 DMC FDA Drug

• 1 other identifier: VPA-202
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 4

Brief Summary

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.

Conditions

Acute Kidney Injury; Ischemia Reperfusion Injury

Keywords

valproic acid; acute kidney injury; ischemia reperfusion injury; hemorrhage; liver transplant

Outcome Measures

Primary Outcomes (1)

• Stage of AKI as assessed by Kidney Disease: Improving Global Outcomes (KDIGO) stage based on serum creatinine (SCr)

  The primary endpoint of AKI as assessed by 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

  Within the first 48 hours after study drug administration

Secondary Outcomes (5)

• Blood lipocalin-2 (LCN2)

  At baseline, 2 hours post reperfusion, 2 hours post ICU admission, and 24 hours post ICU admission, and then daily through day of hospital discharge or Day 7, whichever comes first

• Urine lipocalin-2 (LCN2)

  At baseline, 2 hours post reperfusion, 2 hours post ICU admission, and 24 hours post ICU admission, and then daily through day of hospital discharge or Day 7, whichever comes first

• Incidence of AKI defined by the occurrence of KDIGO stages 1, 2, or 3 based on SCr, or based on urine output (UO) for those subjects with missing SCr

  Within the first 48 hours after study drug administration

• Incidence of AKI defined by SCr increase or for those subjects with missing SCr, UO decrease

  SCr upon ICU admission, at 12 hours, 24 hours, 36 hours, and 48 hours after ICU admission, and then daily through day of hospital discharge or Day 7, whichever comes first; or UO every 6 hours through 48 hours after study drug administration

• Estimated glomerular filtration rate (eGFR) based on SCr and/or cystatin C

  Upon ICU admission, at 12 hours, 24 hours, 36 hours, and 48 hours after ICU admission, and then daily through day of hospital discharge or Day 7, whichever comes first

Other Outcomes (16)

• Serum creatinine (SCr) values

  Upon ICU admission, at 12 hours, 24 hours, 36 hours, and 48 hours after ICU admission, and then daily through day of hospital discharge or Day 7, whichever comes first

• Volume of all fluids and blood products received by the subject

  During and through 48 hours after study drug administration

• Timing of all fluids and blood products received by the subject

  During and through 48 hours after study drug administration

Study Arms (2)

VPA plus SOC

EXPERIMENTAL

A single dose of 140 mg/kg of VPA plus standard of care

Drug: Valproic acid

Placebo plus SOC

PLACEBO COMPARATOR

A single dose of isotonic saline solution plus standard of care

Drug: Isotonic saline solution

Interventions

Valproic acid DRUG

Valproate sodium in 5-ml single-dose vials containing 100 mg/ml of VPA. The appropriate dose of 140 mg/kg, based on the subject's weight at study entry, will be diluted in isotonic saline solution to a final volume of 300 ml for administration

Also known as: valproate sodium

VPA plus SOC

Isotonic saline solution DRUG

Isotonic saline solution consisting of 0.9% sodium chloride in the volume of 300 ml for administration

Placebo plus SOC

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Westat: lead
• United States Department of Defense: collaborator
• Clinipace Worldwide: collaborator

Study Sites (4)

University of California San Francisco

San Francisco, California, 94143, United States

Location

University of Colorado - Denver

Denver, Colorado, 80045, United States

Location

University of Texas Southwest

Dallas, Texas, 75390, United States

Location

Houston Methodist Specialty and Transplant Hospital

Houston, Texas, 77030, United States

Location

Related Publications (5)

• Hilmi IA, Damian D, Al-Khafaji A, Planinsic R, Boucek C, Sakai T, Chang CC, Kellum JA. Acute kidney injury following orthotopic liver transplantation: incidence, risk factors, and effects on patient and graft outcomes. Br J Anaesth. 2015 Jun;114(6):919-26. doi: 10.1093/bja/aeu556. Epub 2015 Feb 10.

  PMID: 25673576 BACKGROUND

• Georgoff PE, Nikolian VC, Bonham T, Pai MP, Tafatia C, Halaweish I, To K, Watcharotone K, Parameswaran A, Luo R, Sun D, Alam HB. Safety and Tolerability of Intravenous Valproic Acid in Healthy Subjects: A Phase I Dose-Escalation Trial. Clin Pharmacokinet. 2018 Feb;57(2):209-219. doi: 10.1007/s40262-017-0553-1.

  PMID: 28497259 BACKGROUND

• Zheng Q, Liu W, Liu Z, Zhao H, Han X, Zhao M. Valproic acid protects septic mice from renal injury by reducing the inflammatory response. J Surg Res. 2014 Nov;192(1):163-9. doi: 10.1016/j.jss.2014.05.030. Epub 2014 May 20.

  PMID: 24948542 BACKGROUND

• Chateauvieux S, Morceau F, Dicato M, Diederich M. Molecular and therapeutic potential and toxicity of valproic acid. J Biomed Biotechnol. 2010;2010:479364. doi: 10.1155/2010/479364. Epub 2010 Jul 29.

  PMID: 20798865 BACKGROUND

• Li Y, Alam HB. Creating a pro-survival and anti-inflammatory phenotype by modulation of acetylation in models of hemorrhagic and septic shock. Adv Exp Med Biol. 2012;710:107-33. doi: 10.1007/978-1-4419-5638-5_11.

  PMID: 22127890 BACKGROUND

MeSH Terms

Conditions

Acute Kidney Injury; Reperfusion Injury; Hemorrhage

Interventions

Valproic Acid

Condition Hierarchy (Ancestors)

Renal Insufficiency; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Vascular Diseases; Cardiovascular Diseases; Postoperative Complications; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Pentanoic Acids; Valerates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Fatty Acids, Volatile; Fatty Acids; Lipids

Study Officials

• Cristina Rabadan-Diehl, PharmD, PhD

  Westat

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: A phase 2, single-dose, multicenter, double-blind, randomized, placebo-controlled study

Study Record Dates

• First Submitted: August 21, 2020
• First Posted: August 28, 2020
• Study Start: January 1, 2022
• Primary Completion: June 1, 2023
• Study Completion: June 1, 2023
• Last Updated: October 29, 2021

Record last verified: 2021-10

Locations

US (4)