The Val-CARD Trial (Val-CARD)

• ClinicalTrials.gov Identifier: NCT03825250
• Recruitment Status: Recruiting
• First Posted: January 31, 2019
• Last Update Posted: May 3, 2021
• Sponsor: University of Leicester
• Information provided by (Responsible Party): University of Leicester

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Cardiac Valve Disease; Coronary Artery Disease; Organ Failure, Multiple	Drug: Sodium Valproate	Phase 1; Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 122 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment

Intervention 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)
• Primary Purpose: Treatment
• Official Title: A Randomised Controlled Trial of Pre-surgery Sodium ValpRoate, for the Prevention of Organ Injury in Cardiac Surgery: THE Val-CARD TRIAL
• Actual Study Start Date: November 6, 2018
• Estimated Primary Completion Date: November 2021
• Estimated Study Completion Date: February 2022

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

1. Change in Multiple organ dysfunction - Sepsis-related Organ Failure Assessment (SOFA) Score) [ Time Frame: Baseline, 4 weeks, 0-6, 24, 48, 72 and 96 hours ]
   Range 0-3, 3 being the worse score
2. NGAL (Neutrophil gelatinase associated lipocalcin) [ Time Frame: Baseline, day before surgery, 6-12, 24 and 48 hours post-surgery. ]
   Measurement of NGAL level and expressed as μg/L.
3. Lung Injury - Arterial alveolar oxygen (PaO2/FiO2) ratios [ Time Frame: Baseline, day before surgery, 24, 48, 72 and 96 hours post-surgery. ]
   Measurement of PaO2/FiO2 ratio and expressed in kPa/L.
4. AST (Aspartate Transaminase) [ Time Frame: Baseline, day before surgery, 0-6, 6-12, 24, 48, 72 and 96 hours post-surgery ]
   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.
5. ALT (Alanine Transaminase) [ Time Frame: Baseline, day before surgery, 0-6, 6-12, 24, 48, 72 and 96 hours post-surgery ]
   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.
6. Bilirubin [ Time Frame: Baseline, day before surgery, 0-6, 6-12, 24, 48, 72 and 96 hours post-surgery ]
   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.
7. Alkaline Phosphatase [ Time Frame: Baseline, day before surgery, 0-6, 6-12, 24, 48, 72 and 96 hours post-surgery ]
   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.
8. Serum Amylase [ Time Frame: Baseline, day before surgery, 0-6, 6-12, 24, 48, 72 and 96 hours post-surgery ]
   Measurement of Amylase levels in serum and expressed in IU/L. Acute pancreatitis will be defined as a serum amylase concentration >1000 ng/ml.
9. Assessment of resource use - Time until extubation [ Time Frame: Time (hours) measured from the start of surgery - to extubation (up to 30 days) ]
10. Length of stay in Intensive Care Unit [ Time Frame: Time (hours) measured from the start of surgery to discharge from ICU (up to 30 days) ]
    Number of hours between admission and discharge from the Intensive Care Unit (ICU).
11. Length of Stay in Hospital [ Time Frame: Time (days) measured from the start of surgery to discharge from hospital (up to 90 days) ]
    Number of days between the date of surgery and discharge from the hospital.
12. Sepsis [ Time Frame: Baseline, 4 weeks before surgery, 0-6, 6-12, 24, 48, 72 and 96 hours post-surgery ]
    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.
13. Rate of mortality [ Time Frame: Within 30-days from surgery and at 1 year from surgery ]
    Rate of mortality at 30-day and 1 year from the date of surgery.
14. Bleeding and Transfusion [ Time Frame: Intra-operative and between time of surgery and hospital discharge up to two weeks ]
    The total number of units of red cells and other blood components transfused during the operative period and post-operative hospital stay
15. Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: Post-operative up to 3 months follow-up from time of surgery ]
    Adverse events as assessed for type and severity by CTCAE v4.0
16. Mechanism study: Mithocondrial function of microvessels from tissue biopsies [ Time Frame: At time of surgery ]
    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.
17. Mechanism study: microRNAs isolation from microvessels [ Time Frame: At time of surgery ]
    The findings will be represented by the frequency (%) of identified microRNAs. 50-100 mg biopsies obtained from pedicled left internal mammary artery biopsies.
18. Mechanism study: Chromatin Immunoprecipitation (ChIP) of microvessels from tissue biopsies [ Time Frame: 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. 50-100 mg biopsies obtained from pedicled left internal mammary artery biopsies.

19. Mechanism study: Mithocondrial function measured in right atrium myocardium tissue biopsies [ Time Frame: At time of surgery ]
    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.
20. Mechanism study: microRNA isolation from right atrium myocardium tissue biopsies [ Time Frame: At time of surgery ]
    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.
21. Mechanism study: Chromatin Immunoprecipitation (ChIP) in right atrium myocardium tissue biopsies [ Time Frame: At time of surgery ]

    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.

22. Mechanism study: Mithocondrial function measured in adipose tissue biopsies [ Time Frame: At time of surgery ]
    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.
23. Mechanism study: microRNA isolation in adipose tissue biopsies [ Time Frame: At time of surgery ]
    Adipose tissue collected from epicardial fat at time of surgery. The findings will be represented by the frequency (%) of identified microRNAs.
24. Mechanism study: Chromatin Immunoprecipitation (ChIP) in adipose tissue biopsies [ Time Frame: At time of surgery ]

    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.

25. Mechanism study: Measurement of microvesicles in urine samples [ Time Frame: 1 day before surgery, 12 and 24 hours following surgery ]
    Identification of microvesicles. The findings will be represented by the frequency (%) of each identified microvesicle.
26. Mechanism study: Measurement of microRNAs in urine samples [ Time Frame: 1 day before surgery, 12 and 24 hours following surgery ]
    The findings will be represented by the frequency (%) of identified microRNAs.
27. Mechanism study: Measurement of histone acetylation in urine samples [ Time Frame: 1 day before surgery, 12 and 24 hours following surgery ]
    The findings will be reported as acetylated H3 (ug/mg) over time (hours)
28. Mechanism study: Measurement of gene expression in urine samples [ Time Frame: 1 day before surgery, 12 and 24 hours following surgery ]
    Whole genome sequencing will be achieved through ATAC sequencing. The identified genes will be characterised by average expression count over ATAC.
29. Mechanism study: Cardiac Magnetic Resonance Imaging - Cardiac Function [ Time Frame: Baseline, 1 day before surgery and 3 months following surgery ]
    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.
30. Mechanism study: Cardiac Magnetic Resonance Imaging - Cardiac adiposity content [ Time Frame: Baseline, 1 day before surgery and 3 months following surgery ]
    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.
31. Mechanism study: Cardiac Magnetic Resonance Imaging - Visceral adiposity content [ Time Frame: Baseline, 1 day before surgery and 3 months following surgery ]
    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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Contacts

Contact: Marius Roman, MD; +44(0)1162525841; mariusroman@nhs.net

Contact: Hardeep Aujla; 0116250 ext 2650; ha200@le.ac.uk

Locations

United Kingdom

Glenfield Hospital; Recruiting

Leicester, Leicestershire, United Kingdom, LE3 9QP

Contact: Marius Roman, MD (Cantab) 0116250 ext 2650 mariusroman@nhs.net

Contact: Hardeep Aujla 0116250 ext 2650 ha200@le.ac.uk

Sub-Investigator: Ricardo Abbasciano, MD

Sub-Investigator: Douglas Miller, MD

Sponsors and Collaborators

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

More Information

• Responsible Party: University of Leicester
• ClinicalTrials.gov Identifier: NCT03825250
• Other Study ID Numbers: 0667; 2018-002076-41 ( EudraCT Number ); 246126 ( Registry Identifier: IRAS ); 18/EM/0188 ( Other Identifier: REC East Midlands )
• First Posted: January 31, 2019
• Last Update Posted: May 3, 2021
• Last Verified: April 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by University of Leicester:

Sodium Valproate; Cardiac Surgery; Organ Injury Prevention

Additional relevant MeSH terms:

Coronary Artery Disease; Heart Valve Diseases; Multiple Organ Failure; Coronary Disease; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases; Shock; Pathologic Processes; 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