Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04531592
Recruitment Status : Withdrawn (Study terminated by the Sponsor)
First Posted : August 28, 2020
Last Update Posted : October 29, 2021
Sponsor:
Collaborators:
United States Department of Defense
Clinipace Worldwide
Information provided by (Responsible Party):
Westat

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.

Condition or disease Intervention/treatment Phase
Acute Kidney Injury Ischemia Reperfusion Injury Drug: Valproic acid Drug: Isotonic saline solution Phase 2

Show Show detailed description

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 0 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: A phase 2, single-dose, multicenter, double-blind, randomized, placebo-controlled study
Masking: Triple (Participant, Care Provider, Investigator)
Masking Description: 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.
Primary Purpose: Treatment
Official Title: 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
Estimated Study Start Date : January 2022
Estimated Primary Completion Date : June 2023
Estimated Study Completion Date : June 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: VPA plus SOC
A single dose of 140 mg/kg of VPA plus standard of care
Drug: Valproic acid
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
Other Name: valproate sodium

Placebo Comparator: Placebo plus SOC
A single dose of isotonic saline solution plus standard of care
Drug: Isotonic saline solution
Isotonic saline solution consisting of 0.9% sodium chloride in the volume of 300 ml for administration




Primary Outcome Measures :
  1. Stage of AKI as assessed by Kidney Disease: Improving Global Outcomes (KDIGO) stage based on serum creatinine (SCr) [ Time Frame: Within the first 48 hours after study drug administration ]
    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


Secondary Outcome Measures :
  1. Blood lipocalin-2 (LCN2) [ Time Frame: 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 ]
    LCN2 is an early biomarker of AKI

  2. Urine lipocalin-2 (LCN2) [ Time Frame: 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 ]
    LCN2 is an early biomarker of AKI

  3. 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 [ Time Frame: Within the first 48 hours after study drug administration ]
    Incidence of AKI defined by KDIGO stages where stage 0 is no occurrence of AKI and stages 1, 2, or 3 is occurrence of AKI. KDIGO staging will be based on SCr, or based on urine output (UO) for those subjects with missing SCr

  4. Incidence of AKI defined by SCr increase or for those subjects with missing SCr, UO decrease [ Time Frame: 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 ]
    Incidence of AKI define by increase in SCr by ≥ 0.3 mg/ dl within 48 hours after study drug administration; or an increase in SCr to ≥ 1.5 times baseline anytime within the 7 days after study drug administration; or for those subjects with missing SCr, UO volume < 0.5 ml/kg/h for 6 hours

  5. Estimated glomerular filtration rate (eGFR) based on SCr and/or cystatin C [ Time Frame: 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 ]
    eGFR to be calculated based on SCr and/or cystatin C using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation


Other Outcome Measures:
  1. Serum creatinine (SCr) values [ Time Frame: 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 ]
    Changes in SCr values through day of hospital discharge or Day 7 after study drug administration, whichever comes first

  2. Volume of all fluids and blood products received by the subject [ Time Frame: During and through 48 hours after study drug administration ]
    Volume of all fluids and blood products (including red blood cells (RBC), packed RBC, fresh frozen plasma, platelet, cryoprecipitate, and clotting factors) received by the subject

  3. Timing of all fluids and blood products received by the subject [ Time Frame: During and through 48 hours after study drug administration ]
    Timing of all fluids and blood products (including red blood cells (RBC), packed RBC, fresh frozen plasma, platelet, cryoprecipitate, and clotting factors) received by the subject

  4. Acute Physiology and Chronic Health Evaluation II (APACHE II) score [ Time Frame: Daily through day of hospital discharge or Day 7, whichever comes first ]
    APACHE II score (minimum score = 0; maximum score = 71) as an assessment of disease severity. Higher score is associated with worst outcome

  5. Intensive care unit (ICU) and/or stepdown unit (SDU) stay [ Time Frame: Through Day 7 after study drug administration ]
    Length of time the subject remained in the ICU and/or SDU

  6. Hospital stay [ Time Frame: Through Day 7 after study drug administration ]
    Length of time the subject remained hospitalized

  7. Renal replacement therapy (RRT) [ Time Frame: Through Day 7 after study drug administration ]
    Incidence of RRT the subject required after study drug administration

  8. Alive and ventilator free days (aVFD) [ Time Frame: Through Day 7 after study drug administration ]
    Number of days that the subject was alive and ventilator free

  9. Patient survival [ Time Frame: Through Day 7 after study drug administration ]
    Whether or not subject is alive on Day 7 after study drug administration

  10. Allograft survival [ Time Frame: Through Day 7 after study drug administration ]
    Whether or not the allograft is alive on Day 7 after study drug administration

  11. Myocardial injury [ Time Frame: 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 ]
    Number of subjects with myocardial injury defined by troponin I level greater than 0.04 nanogram/milliliter

  12. Clavien-Dindo Classification [ Time Frame: Daily through day of hospital discharge or Day 7, whichever comes first ]
    Clavien-Dindo classification (minimum grade = I; maximum grade = V) as a measure of surgical complication. Higher grade is associated with worst outcome

  13. Treatment-emergent adverse events (TEAEs) [ Time Frame: After study drug administration through Day 7 ]
    Incidence of TEAEs

  14. Adverse events of special interest (AESIs) [ Time Frame: After study drug administration through Day 7 ]
    Incidence of AESIs after a single infusion of VPA

  15. Serious adverse events (SAEs) [ Time Frame: After study drug administration through Day 7 ]
    Incidence of SAEs

  16. Deaths [ Time Frame: After study drug administration through Day 7 ]
    Incidence of deaths



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04531592


Locations
Layout table for location information
United States, California
University of California San Francisco
San Francisco, California, United States, 94143
United States, Colorado
University of Colorado - Denver
Denver, Colorado, United States, 80045
United States, Texas
University of Texas Southwest
Dallas, Texas, United States, 75390
Houston Methodist Specialty and Transplant Hospital
Houston, Texas, United States, 77030
Sponsors and Collaborators
Westat
United States Department of Defense
Clinipace Worldwide
Investigators
Layout table for investigator information
Principal Investigator: Cristina Rabadan-Diehl, PharmD, PhD Westat
Publications:
Layout table for additonal information
Responsible Party: Westat
ClinicalTrials.gov Identifier: NCT04531592    
Other Study ID Numbers: VPA-202
First Posted: August 28, 2020    Key Record Dates
Last Update Posted: October 29, 2021
Last Verified: October 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Westat:
valproic acid
acute kidney injury
ischemia reperfusion injury
hemorrhage
liver transplant
Additional relevant MeSH terms:
Layout table for MeSH terms
Acute Kidney Injury
Reperfusion Injury
Ischemia
Wounds and Injuries
Pathologic Processes
Renal Insufficiency
Kidney Diseases
Urologic Diseases
Vascular Diseases
Cardiovascular Diseases
Postoperative Complications
Valproic Acid
Anticonvulsants
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
GABA Agents
Neurotransmitter Agents
Physiological Effects of Drugs
Antimanic Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs