The Val-CARD Trial

Study Overview
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Brief Summary
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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.

Detailed Description
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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: GROUP A: Standard care (no treatment) GROUP B: Sodium valproate at a target dose of 15 mg/kg per day for 1-2 weeks pre-surgery. Group C: Sodium valproate at a target dose of 15 mg/kg per day for 4-6 weeks pre-surgery. 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: GROUP A: Standard care (no treatment) 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: Pre-surgery sodium valproate will reduce the risk of post cardiac surgery organ failure. 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. 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. 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. Sodium valproate will reduce the risk of post cardiac surgery endothelial dysfunction by increasing the expression of genes that promote endothelial homeostasis. The trial interventions will be tolerated by patients and will not result in long-term adverse changes in cardiometabolic status.

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

Conditions
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Cardiac Valve Disease, Coronary Artery Disease, Organ Failure, Multiple

Intervention / Treatment
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* Drug: Sodium Valproate


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Unblinded two phased randomised controlled trial Discovery phase: 4 groups (1 control, 3 treatment) Efficiency phase: 2 groups (1 control, 1 treatment)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Group A: Control<br>Standard of care | |
| Experimental: Group B: Sodium Valproate Treatment<br>15 mg/kg for 1-2 weeks | Drug: Sodium Valproate<br>* 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<br>|
| Experimental: Group C: Sodium Valproate Treatment<br>15 mg/kg for 4-6 weeks | Drug: Sodium Valproate<br>* 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<br>|
| Experimental: Group D: Sodium Valproate Treatment<br>25 mg/kg for 4-6 weeks | Drug: Sodium Valproate<br>* 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<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cardiac Surgery, Sodium Valproate, Organ Injury Prevention