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

NCT04531579 | Withdrawn Phase 2 DMC FDA Drug

• 1 other identifier: VPA-201
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 2

Brief Summary

The purpose of this study is to find out if a drug called valproic acid (VPA) will protect organs (such as the kidneys) from damage when a person is injured and loses a large amount of blood. The organs may not get enough blood or oxygen when a patient loses a lot of blood. After the patient receives fluids such as blood, plasma, or saline and the bleeding is stopped, blood and oxygen return to the organs. This process called ischemia/reperfusion (I/R) is known to cause injury to organs such as the kidneys and heart. VPA is an approved drug for treating conditions like 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 trauma 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 trauma patients normally receive to treat their injuries. 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; trauma

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, 4 hours, and 24 hours from the end of infusion, and then daily through day of hospital discharge or Day 7, whichever comes first

• Urine lipocalin-2 (LCN2)

  At baseline, 2 hours, 4 hours, and 24 hours after study drug administration, 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 at 1 hour, 12 hours, 24 hours, 36 hours, and 48 hours after study drug administration, 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

  At 1 hour, 12 hours, 24 hours, 36 hours, and 48 hours after study drug administration, and then daily through day of hospital discharge or Day 7, whichever comes first

Other Outcomes (14)

• Serum creatinine (SCr) values

  At 1 hour, 12 hours, 24 hours, 36 hours, and 48 hours after study drug administration, 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

  At time of ED arrival through 48 hours after study drug administration

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

  At time of ED arrival 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 Solution

Placebo plus SOC

PLACEBO COMPARATOR

A single dose of isotonic saline solution plus standard of care

Drug: Isotonic saline solution

Interventions

Valproic Acid Solution 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

Also known as: saline solution

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;
• Injuries or underlying medical problems are considered likely survivable by the attending trauma physician on initial evaluation; and
• Experienced blunt or penetrating trauma that resulted in bleeding with at least two systolic blood pressure (SBP) readings ≤100 mmHg at any point during transport to the ED or during the Screening period. SBP readings of ≤100 mmHg need not be consecutive.

You may not qualify if:

• Has a known history of adverse reaction to VPA;
• Is currently receiving VPA;
• Is pregnant or breastfeeding;
• Has inadequate venous access;
• Is in need of a kidney transplant, or currently on RRT for either AKI or hepato-renal syndrome, type I (HRS-I);
• Is known to have mitochondrial disorders caused by polymerase γ (POLG) mutations;
• Is currently incarcerated or pending incarceration;
• Has a known history of hepatic dysfunction (defined as Model for End-Stage Liver Disease (MELD) score \>15), pancreatitis (recurrent, recent, or severe), or renal insufficiency (defined as SCr result \>2.0 mg/dl);
• Has non-survivable injuries based on the judgement of the attending trauma physician (e.g., pre-hospital cardiac arrest);
• Has non-hemorrhagic etiologies of shock (e.g., neurogenic, cardiogenic, septic, drowning, hanging, etc.);
• Has second or third degree burns of any size or location;
• Has severe trauma brain injury (TBI) defined as a positive head computed tomography (CT) scan and a score of less than eight on the Glasgow Coma Scale (GCS); 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 (2)

University of Maryland - Baltimore

Baltimore, Maryland, 21201, United States

Location

University of Washington

Seattle, Washington, 98104, United States

Location

Related Publications (8)

• Bihorac A, Delano MJ, Schold JD, Lopez MC, Nathens AB, Maier RV, Layon AJ, Baker HV, Moldawer LL. Incidence, clinical predictors, genomics, and outcome of acute kidney injury among trauma patients. Ann Surg. 2010 Jul;252(1):158-65. doi: 10.1097/SLA.0b013e3181deb6bc.

  PMID: 20562612 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

• Costantini TW, Fraga G, Fortlage D, Wynn S, Fraga A, Lee J, Doucet J, Bansal V, Coimbra R. Redefining renal dysfunction in trauma: implementation of the Acute Kidney Injury Network staging system. J Trauma. 2009 Aug;67(2):283-7; discussion 287-8. doi: 10.1097/TA.0b013e3181a51a51.

  PMID: 19667880 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

• Heegard KD, Stewart IJ, Cap AP, Sosnov JA, Kwan HK, Glass KR, Morrow BD, Latack W, Henderson AT, Saenz KK, Siew ED, Ikizler TA, Chung KK. Early acute kidney injury in military casualties. J Trauma Acute Care Surg. 2015 May;78(5):988-93. doi: 10.1097/TA.0000000000000607.

  PMID: 25909420 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

• Wu MY, Yiang GT, Liao WT, Tsai AP, Cheng YL, Cheng PW, Li CY, Li CJ. Current Mechanistic Concepts in Ischemia and Reperfusion Injury. Cell Physiol Biochem. 2018;46(4):1650-1667. doi: 10.1159/000489241. Epub 2018 Apr 20.

  PMID: 29694958 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

MeSH Terms

Conditions

Acute Kidney Injury; Reperfusion Injury; Hemorrhage; Wounds and Injuries

Interventions

Valproic Acid; Saline Solution

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; Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

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 (2)