<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03825250</url>
  </required_header>
  <id_info>
    <org_study_id>0667</org_study_id>
    <secondary_id>2018-002076-41</secondary_id>
    <secondary_id>246126</secondary_id>
    <secondary_id>18/EM/0188</secondary_id>
    <nct_id>NCT03825250</nct_id>
  </id_info>
  <brief_title>The Val-CARD Trial</brief_title>
  <acronym>Val-CARD</acronym>
  <official_title>A Randomised Controlled Trial of Pre-surgery Sodium ValpRoate, for the Prevention of Organ Injury in Cardiac Surgery: THE Val-CARD TRIAL</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Leicester</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Leicester</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The Val-CARD trial aims to answer the question: &quot;Does the drug sodium valproate reduce&#xD;
      complications affecting the heart and kidneys in patients having heart operations?&quot; Sodium&#xD;
      valproate is a drug commonly used in the treatment of epilepsy. Recently it has been shown to&#xD;
      protect against heart and kidney damage in laboratory tests. This has led to trials&#xD;
      evaluating whether it can prevent heart and kidney damage in patients. The investigators wish&#xD;
      to evaluate whether treatment with sodium valproate for a short period can reduce levels of&#xD;
      organ damage following heart surgery by measuring this in blood tests, exercise tests, a&#xD;
      special x-ray measuring body fat content, a walk exercise and muscle strength tests. The&#xD;
      investigators now want to establish if sodium valproate works by making the heart and kidney&#xD;
      more resistant to any injury that results from the use of the heart lung machine.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This trial is a single centre, unblinded, randomised controlled trial of pre-surgery sodium&#xD;
      valproate versus standard care (no treatment). The trial has two phases. In the first phase -&#xD;
      the dose finding phase, 40 patients will be randomised (1:1:1:1) to three different treatment&#xD;
      doses versus a control group of standard care (no treatment). A single sodium valproate dose&#xD;
      will be selected based on the evaluation of compliance, toxicity and levels of Histone&#xD;
      Deacetylase inhibition. In the second phase, the efficacy of this dose at preventing&#xD;
      myocardial and kidney injury will then be compared to untreated controls using a 1:1&#xD;
      randomised parallel group design in a further 82 patients. In an optional research procedure&#xD;
      during the efficacy phase of the trial (Phase 2) cardiometabolic status (cardiac function and&#xD;
      visceral adiposity) will be evaluated using MRI scanning.&#xD;
&#xD;
      Patients will be screened by the investigators to assess eligibility for entry into the&#xD;
      trial. Eligible patients undergoing cardiac surgery with CPB who consent to participate will&#xD;
      be randomly allocated using concealed allocation as follows:&#xD;
&#xD;
      In the dose finding phase of the trial patient will be randomised in a 1:1:1:1 ratio to:&#xD;
&#xD;
        1. GROUP A: Standard care (no treatment)&#xD;
&#xD;
        2. GROUP B: Sodium valproate at a target dose of 15 mg/kg per day for 1-2 weeks&#xD;
           pre-surgery.&#xD;
&#xD;
        3. Group C: Sodium valproate at a target dose of 15 mg/kg per day for 4-6 weeks&#xD;
           pre-surgery.&#xD;
&#xD;
        4. Group D: Sodium valproate at a target dose of 25 mg/kg per day for 4-6 weeks&#xD;
           pre-surgery.&#xD;
&#xD;
      In the efficacy phase of the trial patients will be randomised in a 1:1 ratio to:&#xD;
&#xD;
        1. GROUP A: Standard care (no treatment)&#xD;
&#xD;
        2. GROUP B, C or D: Sodium valproate at a target dose as determined by the dose finding&#xD;
           phase of the trial.&#xD;
&#xD;
      The Val-CARD Trial proposes to test the overarching hypothesis that pre-surgery&#xD;
      administration of sodium valproate will protect patients against organ damage that occurs&#xD;
      during cardiac surgery with cardiopulmonary bypass.&#xD;
&#xD;
      The trial will test a number of specific hypotheses:&#xD;
&#xD;
        1. Pre-surgery sodium valproate will reduce the risk of post cardiac surgery organ failure.&#xD;
&#xD;
        2. Short-term (1-2 weeks) pre-surgery treatment with sodium valproate at a target dose of&#xD;
           15mg/kg/day will have different pharmacokinetics but comparable tolerability and&#xD;
           protective effects on myocardial and renal signaling to long-term (4-6 weeks) treatment&#xD;
           at a target dose of 15mg/kg/ day or 25mg/kg/day.&#xD;
&#xD;
        3. Sodium valproate will reduce the risk of post cardiac surgery myocardial injury by&#xD;
           increasing the expression of genes that promote myocardial mitochondrial homeostasis via&#xD;
           effects on chromatin histone deacetylation.&#xD;
&#xD;
        4. Sodium valproate will reduce the risk of post cardiac surgery acute kidney injury (AKI)&#xD;
           by increasing the expression of genes that promote renal tubular homeostasis.&#xD;
&#xD;
        5. Sodium valproate will reduce the risk of post cardiac surgery endothelial dysfunction by&#xD;
           increasing the expression of genes that promote endothelial homeostasis.&#xD;
&#xD;
        6. The trial interventions will be tolerated by patients and will not result in long-term&#xD;
           adverse changes in cardiometabolic status.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">November 6, 2018</start_date>
  <completion_date type="Anticipated">February 2022</completion_date>
  <primary_completion_date type="Anticipated">November 2021</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Unblinded two phased randomised controlled trial&#xD;
Discovery phase: 4 groups (1 control, 3 treatment)&#xD;
Efficiency phase: 2 groups (1 control, 1 treatment)</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change of Serum Creatinine level</measure>
    <time_frame>Baseline, 2 weeks, 4 weeks, 0-6, 6-12, 24, 48, 72, and 96 hours post-operatively</time_frame>
    <description>Measurement of serum creatinine level and expressed as umol/L.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change of Serum Troponin I level</measure>
    <time_frame>Baseline, at 0-6, 6-12, 24, 48 and 72 hours post-operatively</time_frame>
    <description>Measurement of serum Troponin level and expressed as ng/L.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in Multiple organ dysfunction - Sepsis-related Organ Failure Assessment (SOFA) Score)</measure>
    <time_frame>Baseline, 4 weeks, 0-6, 24, 48, 72 and 96 hours</time_frame>
    <description>Range 0-3, 3 being the worse score</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>NGAL (Neutrophil gelatinase associated lipocalcin)</measure>
    <time_frame>Baseline, day before surgery, 6-12, 24 and 48 hours post-surgery.</time_frame>
    <description>Measurement of NGAL level and expressed as μg/L.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Lung Injury - Arterial alveolar oxygen (PaO2/FiO2) ratios</measure>
    <time_frame>Baseline, day before surgery, 24, 48, 72 and 96 hours post-surgery.</time_frame>
    <description>Measurement of PaO2/FiO2 ratio and expressed in kPa/L.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>AST (Aspartate Transaminase)</measure>
    <time_frame>Baseline, day before surgery, 0-6, 6-12, 24, 48, 72 and 96 hours post-surgery</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>ALT (Alanine Transaminase)</measure>
    <time_frame>Baseline, day before surgery, 0-6, 6-12, 24, 48, 72 and 96 hours post-surgery</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Bilirubin</measure>
    <time_frame>Baseline, day before surgery, 0-6, 6-12, 24, 48, 72 and 96 hours post-surgery</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Alkaline Phosphatase</measure>
    <time_frame>Baseline, day before surgery, 0-6, 6-12, 24, 48, 72 and 96 hours post-surgery</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum Amylase</measure>
    <time_frame>Baseline, day before surgery, 0-6, 6-12, 24, 48, 72 and 96 hours post-surgery</time_frame>
    <description>Measurement of Amylase levels in serum and expressed in IU/L. Acute pancreatitis will be defined as a serum amylase concentration &gt;1000 ng/ml.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of resource use - Time until extubation</measure>
    <time_frame>Time (hours) measured from the start of surgery - to extubation (up to 30 days)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Length of stay in Intensive Care Unit</measure>
    <time_frame>Time (hours) measured from the start of surgery to discharge from ICU (up to 30 days)</time_frame>
    <description>Number of hours between admission and discharge from the Intensive Care Unit (ICU).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Length of Stay in Hospital</measure>
    <time_frame>Time (days) measured from the start of surgery to discharge from hospital (up to 90 days)</time_frame>
    <description>Number of days between the date of surgery and discharge from the hospital.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Sepsis</measure>
    <time_frame>Baseline, 4 weeks before surgery, 0-6, 6-12, 24, 48, 72 and 96 hours post-surgery</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of mortality</measure>
    <time_frame>Within 30-days from surgery and at 1 year from surgery</time_frame>
    <description>Rate of mortality at 30-day and 1 year from the date of surgery.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Bleeding and Transfusion</measure>
    <time_frame>Intra-operative and between time of surgery and hospital discharge up to two weeks</time_frame>
    <description>The total number of units of red cells and other blood components transfused during the operative period and post-operative hospital stay</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of participants with treatment-related adverse events as assessed by CTCAE v4.0</measure>
    <time_frame>Post-operative up to 3 months follow-up from time of surgery</time_frame>
    <description>Adverse events as assessed for type and severity by CTCAE v4.0</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mechanism study: Mithocondrial function of microvessels from tissue biopsies</measure>
    <time_frame>At time of surgery</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mechanism study: microRNAs isolation from microvessels</measure>
    <time_frame>At time of surgery</time_frame>
    <description>The findings will be represented by the frequency (%) of identified microRNAs. 50-100 mg biopsies obtained from pedicled left internal mammary artery biopsies.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mechanism study: Chromatin Immunoprecipitation (ChIP) of microvessels from tissue biopsies</measure>
    <time_frame>At time of surgery</time_frame>
    <description>To identify protein binding sites that may help identify functional elements in the genome.&#xD;
Findings will be represented by the number (n) of binding sites. 50-100 mg biopsies obtained from pedicled left internal mammary artery biopsies.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mechanism study: Mithocondrial function measured in right atrium myocardium tissue biopsies</measure>
    <time_frame>At time of surgery</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mechanism study: microRNA isolation from right atrium myocardium tissue biopsies</measure>
    <time_frame>At time of surgery</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mechanism study: Chromatin Immunoprecipitation (ChIP) in right atrium myocardium tissue biopsies</measure>
    <time_frame>At time of surgery</time_frame>
    <description>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.&#xD;
Findings will be represented by the number (n) of binding sites.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mechanism study: Mithocondrial function measured in adipose tissue biopsies</measure>
    <time_frame>At time of surgery</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mechanism study: microRNA isolation in adipose tissue biopsies</measure>
    <time_frame>At time of surgery</time_frame>
    <description>Adipose tissue collected from epicardial fat at time of surgery. The findings will be represented by the frequency (%) of identified microRNAs.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mechanism study: Chromatin Immunoprecipitation (ChIP) in adipose tissue biopsies</measure>
    <time_frame>At time of surgery</time_frame>
    <description>Adipose tissue collected from epicardial fat at time of surgery. To identify protein binding sites that may help identify functional elements in the genome.&#xD;
Findings will be represented by the number (n) of binding sites.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mechanism study: Measurement of microvesicles in urine samples</measure>
    <time_frame>1 day before surgery, 12 and 24 hours following surgery</time_frame>
    <description>Identification of microvesicles. The findings will be represented by the frequency (%) of each identified microvesicle.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mechanism study: Measurement of microRNAs in urine samples</measure>
    <time_frame>1 day before surgery, 12 and 24 hours following surgery</time_frame>
    <description>The findings will be represented by the frequency (%) of identified microRNAs.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mechanism study: Measurement of histone acetylation in urine samples</measure>
    <time_frame>1 day before surgery, 12 and 24 hours following surgery</time_frame>
    <description>The findings will be reported as acetylated H3 (ug/mg) over time (hours)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mechanism study: Measurement of gene expression in urine samples</measure>
    <time_frame>1 day before surgery, 12 and 24 hours following surgery</time_frame>
    <description>Whole genome sequencing will be achieved through ATAC sequencing. The identified genes will be characterised by average expression count over ATAC.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mechanism study: Cardiac Magnetic Resonance Imaging - Cardiac Function</measure>
    <time_frame>Baseline, 1 day before surgery and 3 months following surgery</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mechanism study: Cardiac Magnetic Resonance Imaging - Cardiac adiposity content</measure>
    <time_frame>Baseline, 1 day before surgery and 3 months following surgery</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mechanism study: Cardiac Magnetic Resonance Imaging - Visceral adiposity content</measure>
    <time_frame>Baseline, 1 day before surgery and 3 months following surgery</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Anticipated">122</enrollment>
  <condition>Cardiac Valve Disease</condition>
  <condition>Coronary Artery Disease</condition>
  <condition>Organ Failure, Multiple</condition>
  <arm_group>
    <arm_group_label>Group A: Control</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Standard of care</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group B: Sodium Valproate Treatment</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>15 mg/kg for 1-2 weeks</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group C: Sodium Valproate Treatment</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>15 mg/kg for 4-6 weeks</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group D: Sodium Valproate Treatment</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>25 mg/kg for 4-6 weeks</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Sodium Valproate</intervention_name>
    <description>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</description>
    <arm_group_label>Group B: Sodium Valproate Treatment</arm_group_label>
    <arm_group_label>Group C: Sodium Valproate Treatment</arm_group_label>
    <arm_group_label>Group D: Sodium Valproate Treatment</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Adult cardiac surgery patients (≥18 years) undergoing cardiac surgery (CABG, Valve, or&#xD;
             CABG and Valve) with cardiopulmonary bypass (CPB).&#xD;
&#xD;
          -  Able, in the opinion of the investigator, and willing to give informed consent.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Emergency or salvage procedure&#xD;
&#xD;
          -  Patients with end stage renal failure defined as an estimated Glomerular Filtration&#xD;
             rate (eGFR) &lt;15 mL/min/1.72 m2 calculated from the Modification of Diet in Renal&#xD;
             Disease equation,1 or patients who are on long-term haemodialysis or have undergone&#xD;
             renal transplantation.&#xD;
&#xD;
          -  Patients with persistent or chronic atrial fibrillation.&#xD;
&#xD;
          -  Patients with acute liver disease.&#xD;
&#xD;
          -  Personal or family history of severe hepatic dysfunction, especially drug related.&#xD;
&#xD;
          -  Patients allergic to sodium valproate.&#xD;
&#xD;
          -  Patients with thrombocytopaenia (platelet count &lt;150x109 per mL).&#xD;
&#xD;
          -  Patients taking long-term Histone Deacetylase Inhibitors such as sodium valproate.&#xD;
&#xD;
          -  Patients taking any of the following medications: antipsychotics, MAO inhibitors,&#xD;
             antidepressants and benzodiazepines, Lithium, Olanzepine, Phenobarbital, Primidone,&#xD;
             Phenytoin, Carbamazepine, Lamotrigine, Felbamate.&#xD;
&#xD;
          -  Patients diagnosed with a mitochondrial deficiency disorder.&#xD;
&#xD;
          -  Patients with porphyria.&#xD;
&#xD;
          -  Patients with known urea cycle disorders.&#xD;
&#xD;
          -  Women of child bearing potential (WOCBP) are excluded from the study. A woman is&#xD;
             defined as being of childbearing potential (WOCBP), i.e. fertile, following menarche&#xD;
             and until becoming post-menopausal, unless permanently sterile. Permanent&#xD;
             sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral&#xD;
             oophorectomy. A postmenopausal state is defined as no menses for 12 months without an&#xD;
             alternative medical cause.&#xD;
&#xD;
          -  Patients who are participating in another interventional clinical trial.&#xD;
&#xD;
          -  Unable, in the opinion of the investigator, or unwilling to give informed consent&#xD;
             protocol.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Gavin Murphy, MD</last_name>
    <role>Study Chair</role>
    <affiliation>BHF Professor of Cardiac Surgery, University of Leicester</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Marius Roman, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Academic Clinical Lecturer in Cardiac Surgery, University of Leicester</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Marius Roman, MD</last_name>
    <phone>+44(0)1162525841</phone>
    <email>mariusroman@nhs.net</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Hardeep Aujla</last_name>
    <phone>0116250</phone>
    <phone_ext>2650</phone_ext>
    <email>ha200@le.ac.uk</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Glenfield Hospital</name>
      <address>
        <city>Leicester</city>
        <state>Leicestershire</state>
        <zip>LE3 9QP</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Marius Roman, MD (Cantab)</last_name>
      <phone>0116250</phone>
      <phone_ext>2650</phone_ext>
      <email>mariusroman@nhs.net</email>
    </contact>
    <contact_backup>
      <last_name>Hardeep Aujla</last_name>
      <phone>0116250</phone>
      <phone_ext>2650</phone_ext>
      <email>ha200@le.ac.uk</email>
    </contact_backup>
    <investigator>
      <last_name>Ricardo Abbasciano, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Douglas Miller, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>April 2021</verification_date>
  <study_first_submitted>August 31, 2018</study_first_submitted>
  <study_first_submitted_qc>January 30, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 31, 2019</study_first_posted>
  <last_update_submitted>April 29, 2021</last_update_submitted>
  <last_update_submitted_qc>April 29, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">May 3, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Sodium Valproate</keyword>
  <keyword>Cardiac Surgery</keyword>
  <keyword>Organ Injury Prevention</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Coronary Artery Disease</mesh_term>
    <mesh_term>Heart Valve Diseases</mesh_term>
    <mesh_term>Multiple Organ Failure</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Valproic Acid</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03825250
org study id: 0667
secondary id: 2018-002076-41
secondary id: 246126
secondary id: 18/EM/0188
nct id: NCT03825250
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
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.
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.
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)
primary purpose: Treatment
masking: None (Open Label)
measure: Change of Serum Creatinine level
time frame: Baseline, 2 weeks, 4 weeks, 0-6, 6-12, 24, 48, 72, and 96 hours post-operatively
description: Measurement of serum creatinine level and expressed as umol/L.
measure: Change of Serum Troponin I level
time frame: Baseline, at 0-6, 6-12, 24, 48 and 72 hours post-operatively
description: Measurement of serum Troponin level and expressed as ng/L.
measure: 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
description: Range 0-3, 3 being the worse score
measure: NGAL (Neutrophil gelatinase associated lipocalcin)
time frame: Baseline, day before surgery, 6-12, 24 and 48 hours post-surgery.
description: Measurement of NGAL level and expressed as μg/L.
measure: Lung Injury - Arterial alveolar oxygen (PaO2/FiO2) ratios
time frame: Baseline, day before surgery, 24, 48, 72 and 96 hours post-surgery.
description: Measurement of PaO2/FiO2 ratio and expressed in kPa/L.
measure: AST (Aspartate Transaminase)
time frame: Baseline, day before surgery, 0-6, 6-12, 24, 48, 72 and 96 hours post-surgery
description: 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.
measure: ALT (Alanine Transaminase)
time frame: Baseline, day before surgery, 0-6, 6-12, 24, 48, 72 and 96 hours post-surgery
description: 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.
measure: Bilirubin
time frame: Baseline, day before surgery, 0-6, 6-12, 24, 48, 72 and 96 hours post-surgery
description: 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.
measure: Alkaline Phosphatase
time frame: Baseline, day before surgery, 0-6, 6-12, 24, 48, 72 and 96 hours post-surgery
description: 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.
measure: Serum Amylase
time frame: Baseline, day before surgery, 0-6, 6-12, 24, 48, 72 and 96 hours post-surgery
description: Measurement of Amylase levels in serum and expressed in IU/L. Acute pancreatitis will be defined as a serum amylase concentration >1000 ng/ml.
measure: Assessment of resource use - Time until extubation
time frame: Time (hours) measured from the start of surgery - to extubation (up to 30 days)
measure: 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)
description: Number of hours between admission and discharge from the Intensive Care Unit (ICU).
measure: Length of Stay in Hospital
time frame: Time (days) measured from the start of surgery to discharge from hospital (up to 90 days)
description: Number of days between the date of surgery and discharge from the hospital.
measure: Sepsis
time frame: Baseline, 4 weeks before surgery, 0-6, 6-12, 24, 48, 72 and 96 hours post-surgery
description: 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.
measure: Rate of mortality
time frame: Within 30-days from surgery and at 1 year from surgery
description: Rate of mortality at 30-day and 1 year from the date of surgery.
measure: Bleeding and Transfusion
time frame: Intra-operative and between time of surgery and hospital discharge up to two weeks
description: The total number of units of red cells and other blood components transfused during the operative period and post-operative hospital stay
measure: 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
description: Adverse events as assessed for type and severity by CTCAE v4.0
measure: Mechanism study: Mithocondrial function of microvessels from tissue biopsies
time frame: At time of surgery
description: 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.
measure: Mechanism study: microRNAs isolation from microvessels
time frame: At time of surgery
description: The findings will be represented by the frequency (%) of identified microRNAs. 50-100 mg biopsies obtained from pedicled left internal mammary artery biopsies.
measure: Mechanism study: Chromatin Immunoprecipitation (ChIP) of microvessels from tissue biopsies
time frame: At time of surgery
description: 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.
measure: Mechanism study: Mithocondrial function measured in right atrium myocardium tissue biopsies
time frame: At time of surgery
description: 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.
measure: Mechanism study: microRNA isolation from right atrium myocardium tissue biopsies
time frame: At time of surgery
description: 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.
measure: Mechanism study: Chromatin Immunoprecipitation (ChIP) in right atrium myocardium tissue biopsies
time frame: At time of surgery
description: 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.
measure: Mechanism study: Mithocondrial function measured in adipose tissue biopsies
time frame: At time of surgery
description: 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.
measure: Mechanism study: microRNA isolation in adipose tissue biopsies
time frame: At time of surgery
description: Adipose tissue collected from epicardial fat at time of surgery. The findings will be represented by the frequency (%) of identified microRNAs.
measure: Mechanism study: Chromatin Immunoprecipitation (ChIP) in adipose tissue biopsies
time frame: At time of surgery
description: 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.
measure: Mechanism study: Measurement of microvesicles in urine samples
time frame: 1 day before surgery, 12 and 24 hours following surgery
description: Identification of microvesicles. The findings will be represented by the frequency (%) of each identified microvesicle.
measure: Mechanism study: Measurement of microRNAs in urine samples
time frame: 1 day before surgery, 12 and 24 hours following surgery
description: The findings will be represented by the frequency (%) of identified microRNAs.
measure: Mechanism study: Measurement of histone acetylation in urine samples
time frame: 1 day before surgery, 12 and 24 hours following surgery
description: The findings will be reported as acetylated H3 (ug/mg) over time (hours)
measure: Mechanism study: Measurement of gene expression in urine samples
time frame: 1 day before surgery, 12 and 24 hours following surgery
description: Whole genome sequencing will be achieved through ATAC sequencing. The identified genes will be characterised by average expression count over ATAC.
measure: Mechanism study: Cardiac Magnetic Resonance Imaging - Cardiac Function
time frame: Baseline, 1 day before surgery and 3 months following surgery
description: 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.
measure: Mechanism study: Cardiac Magnetic Resonance Imaging - Cardiac adiposity content
time frame: Baseline, 1 day before surgery and 3 months following surgery
description: 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.
measure: Mechanism study: Cardiac Magnetic Resonance Imaging - Visceral adiposity content
time frame: Baseline, 1 day before surgery and 3 months following surgery
description: 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.
arm group label: Group A: Control
arm group type: No Intervention
description: Standard of care
arm group label: Group B: Sodium Valproate Treatment
arm group type: Experimental
description: 15 mg/kg for 1-2 weeks
arm group label: Group C: Sodium Valproate Treatment
arm group type: Experimental
description: 15 mg/kg for 4-6 weeks
arm group label: Group D: Sodium Valproate Treatment
arm group type: Experimental
description: 25 mg/kg for 4-6 weeks
intervention type: Drug
intervention name: Sodium Valproate
description: 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
arm group label: Group B: Sodium Valproate Treatment
arm group label: Group C: Sodium Valproate Treatment
arm group label: Group D: Sodium Valproate Treatment
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Gavin Murphy, MD
role: Study Chair
affiliation: BHF Professor of Cardiac Surgery, University of Leicester
last name: Marius Roman, MD
role: Principal Investigator
affiliation: Academic Clinical Lecturer in Cardiac Surgery, University of Leicester
last name: Marius Roman, MD
phone: +44(0)1162525841
email: mariusroman@nhs.net
last name: Hardeep Aujla
phone: 0116250
phone ext: 2650
email: ha200@le.ac.uk
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
investigator: 
country: United Kingdom
responsible party type: Sponsor
mesh term: Coronary Artery Disease
mesh term: Heart Valve Diseases
mesh term: Multiple Organ Failure
mesh term: Valproic Acid
sharing ipd: No