The Val-CARD Trial (Val-CARD)

A Randomised Controlled Trial of Pre-surgery Sodium ValpRoate, for the Prevention of Organ Injury in Cardiac Surgery: THE Val-CARD TRIAL

The Val-CARD trial aims to answer the question: "Does the drug sodium valproate reduce complications affecting the heart and kidneys in patients having heart operations?" Sodium valproate is a drug commonly used in the treatment of epilepsy. Recently it has been shown to protect against heart and kidney damage in laboratory tests. This has led to trials evaluating whether it can prevent heart and kidney damage in patients. The investigators wish to evaluate whether treatment with sodium valproate for a short period can reduce levels of organ damage following heart surgery by measuring this in blood tests, exercise tests, a special x-ray measuring body fat content, a walk exercise and muscle strength tests. The investigators now want to establish if sodium valproate works by making the heart and kidney more resistant to any injury that results from the use of the heart lung machine.

Study Overview

• Status: Recruiting
• Conditions: Coronary Artery Disease; Cardiac Valve Disease; Organ Failure, Multiple
• Intervention / Treatment: Drug: Sodium Valproate

Detailed Description

This trial is a single centre, unblinded, randomised controlled trial of pre-surgery sodium valproate versus standard care (no treatment). The trial has two phases. In the first phase - the dose finding phase, 40 patients will be randomised (1:1:1:1) to three different treatment doses versus a control group of standard care (no treatment). A single sodium valproate dose will be selected based on the evaluation of compliance, toxicity and levels of Histone Deacetylase inhibition. In the second phase, the efficacy of this dose at preventing myocardial and kidney injury will then be compared to untreated controls using a 1:1 randomised parallel group design in a further 82 patients. In an optional research procedure during the efficacy phase of the trial (Phase 2) cardiometabolic status (cardiac function and visceral adiposity) will be evaluated using MRI scanning.

Patients will be screened by the investigators to assess eligibility for entry into the trial. Eligible patients undergoing cardiac surgery with CPB who consent to participate will be randomly allocated using concealed allocation as follows:

In the dose finding phase of the trial patient will be randomised in a 1:1:1:1 ratio to:

1. GROUP A: Standard care (no treatment)
2. GROUP B: Sodium valproate at a target dose of 15 mg/kg per day for 1-2 weeks pre-surgery.
3. Group C: Sodium valproate at a target dose of 15 mg/kg per day for 4-6 weeks pre-surgery.
4. Group D: Sodium valproate at a target dose of 25 mg/kg per day for 4-6 weeks pre-surgery.

In the efficacy phase of the trial patients will be randomised in a 1:1 ratio to:

1. GROUP A: Standard care (no treatment)
2. GROUP B, C or D: Sodium valproate at a target dose as determined by the dose finding phase of the trial.

The Val-CARD Trial proposes to test the overarching hypothesis that pre-surgery administration of sodium valproate will protect patients against organ damage that occurs during cardiac surgery with cardiopulmonary bypass.

The trial will test a number of specific hypotheses:

1. Pre-surgery sodium valproate will reduce the risk of post cardiac surgery organ failure.
2. Short-term (1-2 weeks) pre-surgery treatment with sodium valproate at a target dose of 15mg/kg/day will have different pharmacokinetics but comparable tolerability and protective effects on myocardial and renal signaling to long-term (4-6 weeks) treatment at a target dose of 15mg/kg/ day or 25mg/kg/day.
3. Sodium valproate will reduce the risk of post cardiac surgery myocardial injury by increasing the expression of genes that promote myocardial mitochondrial homeostasis via effects on chromatin histone deacetylation.
4. Sodium valproate will reduce the risk of post cardiac surgery acute kidney injury (AKI) by increasing the expression of genes that promote renal tubular homeostasis.
5. Sodium valproate will reduce the risk of post cardiac surgery endothelial dysfunction by increasing the expression of genes that promote endothelial homeostasis.
6. The trial interventions will be tolerated by patients and will not result in long-term adverse changes in cardiometabolic status.

• Study Type: Interventional
• Enrollment (Anticipated): 122
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Marius Roman, MD; Phone Number: +44(0)1162525841; Email: mariusroman@nhs.net

Study Locations

• United Kingdom
  • Leicestershire
    • Leicester, Leicestershire, United Kingdom, LE3 9QP
      • Recruiting
      • Glenfield Hospital
      • Contact: Marius Roman, MD (Cantab); Phone Number: 2650 0116250; Email: mariusroman@nhs.net
      • Sub-Investigator: Ricardo Abbasciano, MD
      • Sub-Investigator: Douglas Miller, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Adult cardiac surgery patients (≥18 years) undergoing cardiac surgery (CABG, Valve, or CABG and Valve) with cardiopulmonary bypass (CPB).
• Able, in the opinion of the investigator, and willing to give informed consent.

Exclusion Criteria:

• Emergency or salvage procedure
• Patients with end stage renal failure defined as an estimated Glomerular Filtration rate (eGFR) <15 mL/min/1.72 m2 calculated from the Modification of Diet in Renal Disease equation,1 or patients who are on long-term haemodialysis or have undergone renal transplantation.
• Patients with persistent or chronic atrial fibrillation.
• Patients with acute liver disease.
• Personal or family history of severe hepatic dysfunction, especially drug related.
• Patients allergic to sodium valproate.
• Patients with thrombocytopaenia (platelet count <150x109 per mL).
• Patients taking long-term Histone Deacetylase Inhibitors such as sodium valproate.
• Patients taking any of the following medications: antipsychotics, MAO inhibitors, antidepressants and benzodiazepines, Lithium, Olanzepine, Phenobarbital, Primidone, Phenytoin, Carbamazepine, Lamotrigine, Felbamate.
• Patients diagnosed with a mitochondrial deficiency disorder.
• Patients with porphyria.
• Patients with known urea cycle disorders.
• Women of child bearing potential (WOCBP) are excluded from the study. A woman is defined as being of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-menopausal, unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.
• Patients who are participating in another interventional clinical trial.
• Unable, in the opinion of the investigator, or unwilling to give informed consent protocol.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
NO_INTERVENTION: Group A: Control; Standard of care
EXPERIMENTAL: Group B: Sodium Valproate Treatment; 15 mg/kg for 1-2 weeks	Drug: Sodium Valproate; Treatment with Sodium Valproate vs. Control Discovery phase - 4 arms: 15 mg/kg for 1-2 weeks; 15mg/kg for 4-6 weeks; 25 mg/kg for 4-6 weeks; Control Efficiency phase - 2 arms: Treatment group selected from previous phase; Control
EXPERIMENTAL: Group C: Sodium Valproate Treatment; 15 mg/kg for 4-6 weeks	Drug: Sodium Valproate; Treatment with Sodium Valproate vs. Control Discovery phase - 4 arms: 15 mg/kg for 1-2 weeks; 15mg/kg for 4-6 weeks; 25 mg/kg for 4-6 weeks; Control Efficiency phase - 2 arms: Treatment group selected from previous phase; Control
EXPERIMENTAL: Group D: Sodium Valproate Treatment; 25 mg/kg for 4-6 weeks	Drug: Sodium Valproate; Treatment with Sodium Valproate vs. Control Discovery phase - 4 arms: 15 mg/kg for 1-2 weeks; 15mg/kg for 4-6 weeks; 25 mg/kg for 4-6 weeks; Control Efficiency phase - 2 arms: Treatment group selected from previous phase; Control

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change of Serum Creatinine level	Measurement of serum creatinine level and expressed as umol/L.	Baseline, 2 weeks, 4 weeks, 0-6, 6-12, 24, 48, 72, and 96 hours post-operatively
Change of Serum Troponin I level	Measurement of serum Troponin level and expressed as ng/L.	Baseline, at 0-6, 6-12, 24, 48 and 72 hours post-operatively

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Multiple organ dysfunction - Sepsis-related Organ Failure Assessment (SOFA) Score)	Range 0-3, 3 being the worse score	Baseline, 4 weeks, 0-6, 24, 48, 72 and 96 hours
NGAL (Neutrophil gelatinase associated lipocalcin)	Measurement of NGAL level and expressed as μg/L.	Baseline, day before surgery, 6-12, 24 and 48 hours post-surgery.
Lung Injury - Arterial alveolar oxygen (PaO2/FiO2) ratios	Measurement of PaO2/FiO2 ratio and expressed in kPa/L.	Baseline, day before surgery, 24, 48, 72 and 96 hours post-surgery.
AST (Aspartate Transaminase)	Measurement of AST levels in serum and expressed in IU/L. Acute liver injury will be defined as an acute derangement of three times the upper limit of normal.	Baseline, day before surgery, 0-6, 6-12, 24, 48, 72 and 96 hours post-surgery
ALT (Alanine Transaminase)	Measurement of ALT levels in serum and expressed in IU/L. Acute liver injury will be defined as an acute derangement of three times the upper limit of normal.	Baseline, day before surgery, 0-6, 6-12, 24, 48, 72 and 96 hours post-surgery
Bilirubin	Measurement of Bilirubin levels in serum and expressed in μmol/L. Acute liver injury will be defined as an acute derangement of three times the upper limit of normal.	Baseline, day before surgery, 0-6, 6-12, 24, 48, 72 and 96 hours post-surgery
Alkaline Phosphatase	Measurement of Alkaline Phosphatase levels in serum and expressed in IU/L. Acute liver injury will be defined as an acute derangement of three times the upper limit of normal.	Baseline, day before surgery, 0-6, 6-12, 24, 48, 72 and 96 hours post-surgery
Serum Amylase	Measurement of Amylase levels in serum and expressed in IU/L. Acute pancreatitis will be defined as a serum amylase concentration >1000 ng/ml.	Baseline, day before surgery, 0-6, 6-12, 24, 48, 72 and 96 hours post-surgery
Assessment of resource use - Time until extubation		Time (hours) measured from the start of surgery - to extubation (up to 30 days)
Length of stay in Intensive Care Unit	Number of hours between admission and discharge from the Intensive Care Unit (ICU).	Time (hours) measured from the start of surgery to discharge from ICU (up to 30 days)
Length of Stay in Hospital	Number of days between the date of surgery and discharge from the hospital.	Time (days) measured from the start of surgery to discharge from hospital (up to 90 days)
Sepsis	Sepsis is defined as: Suspected or documented infection and an acute change in total Sepsis-related Organ Failure Assessment (SOFA) score ≥2 points consequent to the infection. Range of SOFA is 0 to 3, 3 being the worse score.	Baseline, 4 weeks before surgery, 0-6, 6-12, 24, 48, 72 and 96 hours post-surgery
Rate of mortality	Rate of mortality at 30-day and 1 year from the date of surgery.	Within 30-days from surgery and at 1 year from surgery
Bleeding and Transfusion	The total number of units of red cells and other blood components transfused during the operative period and post-operative hospital stay	Intra-operative and between time of surgery and hospital discharge up to two weeks
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0	Adverse events as assessed for type and severity by CTCAE v4.0	Post-operative up to 3 months follow-up from time of surgery
Mechanism study: Mithocondrial function of microvessels from tissue biopsies	50-100 mg biopsies obtained from pedicled left internal mammary artery biopsies. The mitochondrial function will be measured through the Bioenergetic Health Index. The Bioenergetic Health Index (BHI) is calculated using the following formula: BHI=(ATP-linked×reserve capacity)/(proton leak×non-mitochondrial) - as described by Chacko et al. The expected range is 0-100.	At time of surgery
Mechanism study: microRNAs isolation from microvessels	The findings will be represented by the frequency (%) of identified microRNAs. 50-100 mg biopsies obtained from pedicled left internal mammary artery biopsies.	At time of surgery
Mechanism study: Chromatin Immunoprecipitation (ChIP) of microvessels from tissue biopsies	To identify protein binding sites that may help identify functional elements in the genome. Findings will be represented by the number (n) of binding sites. 50-100 mg biopsies obtained from pedicled left internal mammary artery biopsies.	At time of surgery
Mechanism study: Mithocondrial function measured in right atrium myocardium tissue biopsies	50-100 mg myocardial biopsies will be obtained from the right atrium at surgery. The mitochondrial function will be measured through the Bioenergetic Health Index. The Bioenergetic Health Index (BHI) is calculated using the following formula: BHI=(ATP-linked×reserve capacity)/(proton leak×non-mitochondrial) - as described by Chacko et al. The expected range is 0-100.	At time of surgery
Mechanism study: microRNA isolation from right atrium myocardium tissue biopsies	50-100 mg myocardial biopsies will be obtained from the right atrium at surgery. The findings will be represented by the frequency (%) of identified microRNAs.	At time of surgery
Mechanism study: Chromatin Immunoprecipitation (ChIP) in right atrium myocardium tissue biopsies	50-100 mg myocardial biopsies will be obtained from the right atrium at surgery. To identify protein binding sites that may help identify functional elements in the genome. Findings will be represented by the number (n) of binding sites.	At time of surgery
Mechanism study: Mithocondrial function measured in adipose tissue biopsies	Adipose tissue collected from epicardial fat at time of surgery. The mitochondrial function will be measured through the Bioenergetic Health Index. The Bioenergetic Health Index (BHI) is calculated using the following formula: BHI=(ATP-linked×reserve capacity)/(proton leak×non-mitochondrial) - as described by Chacko et al. The expected range is 0-100.	At time of surgery
Mechanism study: microRNA isolation in adipose tissue biopsies	Adipose tissue collected from epicardial fat at time of surgery. The findings will be represented by the frequency (%) of identified microRNAs.	At time of surgery
Mechanism study: Chromatin Immunoprecipitation (ChIP) in adipose tissue biopsies	Adipose tissue collected from epicardial fat at time of surgery. To identify protein binding sites that may help identify functional elements in the genome. Findings will be represented by the number (n) of binding sites.	At time of surgery
Mechanism study: Measurement of microvesicles in urine samples	Identification of microvesicles. The findings will be represented by the frequency (%) of each identified microvesicle.	1 day before surgery, 12 and 24 hours following surgery
Mechanism study: Measurement of microRNAs in urine samples	The findings will be represented by the frequency (%) of identified microRNAs.	1 day before surgery, 12 and 24 hours following surgery
Mechanism study: Measurement of histone acetylation in urine samples	The findings will be reported as acetylated H3 (ug/mg) over time (hours)	1 day before surgery, 12 and 24 hours following surgery
Mechanism study: Measurement of gene expression in urine samples	Whole genome sequencing will be achieved through ATAC sequencing. The identified genes will be characterised by average expression count over ATAC.	1 day before surgery, 12 and 24 hours following surgery
Mechanism study: Cardiac Magnetic Resonance Imaging - Cardiac Function	Assessment of cardiac function, by assessing ventricular function. This will be expressed as ejection fraction (%). Intravenous contrast will be administered via an indwelling venous catheter.	Baseline, 1 day before surgery and 3 months following surgery
Mechanism study: Cardiac Magnetic Resonance Imaging - Cardiac adiposity content	Assessment of cardiac adiposity content. A percentage of adipose tissue over total body mass will be calculated. Intravenous contrast will be administered via an indwelling venous catheter.	Baseline, 1 day before surgery and 3 months following surgery
Mechanism study: Cardiac Magnetic Resonance Imaging - Visceral adiposity content	Assessment of visceral adiposity content. A percentage of adipose tissue over total body mass will be calculated. Intravenous contrast will be administered via an indwelling venous catheter.	Baseline, 1 day before surgery and 3 months following surgery

Collaborators and Investigators

• Sponsor: University of Leicester
• Investigators: Study Chair: Gavin Murphy, MD, BHF Professor of Cardiac Surgery, University of Leicester; Principal Investigator: Marius Roman, MD, Academic Clinical Lecturer in Cardiac Surgery, University of Leicester

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 6, 2018
• Primary Completion (ANTICIPATED): November 1, 2021
• Study Completion (ANTICIPATED): February 1, 2022

Study Registration Dates

• First Submitted: August 31, 2018
• First Submitted That Met QC Criteria: January 30, 2019
• First Posted (ACTUAL): January 31, 2019

Study Record Updates

• Last Update Posted (ACTUAL): May 3, 2021
• Last Update Submitted That Met QC Criteria: April 29, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Keywords: Cardiac Surgery; Sodium Valproate; Organ Injury Prevention
• Additional Relevant MeSH Terms: Pathologic Processes; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Shock; Coronary Disease; Coronary Artery Disease; Heart Valve Diseases; Multiple Organ Failure; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Enzyme Inhibitors; Tranquilizing Agents; Psychotropic Drugs; GABA Agents; Anticonvulsants; Antimanic Agents; Valproic Acid
• Other Study ID Numbers: 0667; 2018-002076-41 (EUDRACT_NUMBER); 246126 (REGISTRY: IRAS); 18/EM/0188 (OTHER: REC East Midlands)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No