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    Summary
    EudraCT Number:2018-002076-41
    Sponsor's Protocol Code Number:0667
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2018-07-02
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2018-002076-41
    A.3Full title of the trial
    A RANDOMISED CONTROLLED TRIAL OF PRE-SURGERY SODIUM VALPROATE, FOR THE PREVENTION OF ORGAN INJURY IN CARDIAC SURGERY: Val-CARD
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Val-CARD
    A.3.2Name or abbreviated title of the trial where available
    The Val-CARD Trial
    A.4.1Sponsor's protocol code number0667
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03825250
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorUniversity of Leicester
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Epilim Chrono
    D.2.1.1.2Name of the Marketing Authorisation holderAventis Pharma Limited
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameEpilim Chrono
    D.3.4Pharmaceutical form Gastro-resistant tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNSodium Valproate
    D.3.9.1CAS number CHMP
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100 to 500
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Reduction of myocardial and kidney injury risk of post cardiac surgery by increasing the expression of genes that promote myocardial mitochondrial homeostasis via effects on chromatin histone deacetylation.
    E.1.1.1Medical condition in easily understood language
    Decrease of heart and kidney injury following heart surgery.
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10069339
    E.1.2Term Acute kidney injury
    E.1.2System Organ Class 10038359 - Renal and urinary disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10057768
    E.1.2Term Post-cardiac injury syndrome
    E.1.2System Organ Class 100000004849
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The Val-CARD trial tries to answer the question “Does the drug sodium valproate reduce complications affecting the heart and kidneys in patients having heart operations?” through a two phase design, in which the first phase aims to find the optimum dosing regimen that is best tolerated by patients.
    E.2.2Secondary objectives of the trial
    The secondary research questions are: "Does the drug sodium valproate reduce: the failure of multiple organs (like the lungs, kidney or abdominal organs); length of hospital stay; bleeding; infection or death?"
    E.2.3Trial contains a sub-study No
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    In the efficacy phase of the trial patients will undergo optional cardiac MRI scans at baseline, immediately pre-surgery and at three months post-surgery to evaluate myocardial function and visceral adiposity.
    E.3Principal inclusion criteria
    Participant may enter the trial if ALL of the following apply
    1. Adult cardiac surgery patients (≥18 years) undergoing cardiac surgery (CABG, Valve, or CABG and Valve) with cardiopulmonary bypass.
    2. Able, in the opinion of the investigator, and willing to give informed consent.
    E.4Principal exclusion criteria
    Participant may not enter trial if ANY of the following apply:
    1. Emergency or salvage procedure
    2. 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.
    3. Patients with persistent or chronic atrial fibrillation.
    4. Patients with acute liver disease.
    5. Patients with a family history of severe liver disease.
    6. Patients allergic to sodium valproate.
    7. Patients with thrombocytopaenia (platelet count <150x109 per mL).
    8. Patients taking long-term Histone Deacetylase Inhibitors such as sodium valproate.
    9. Patients taking anti-epileptic medication.
    10. Patients diagnosed with a mitochondrial deficiency disorder.
    11. Patients with porphyria.
    12. Patients with known urea cycle disorders.
    13. 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.
    14. Patients who are participating in another interventional clinical trial.
    15. Unable, in the opinion of the investigator, or unwilling to give informed consent protocol.

    Exclusion criteria for optional MRI study
    1. Permanent pacemaker or ICD
    2. Brain Aneurysm Clip
    3. Implanted neural stimulator
    4. Cochlear implant (specific implant must be checked that it is MRI safe)
    5. Ocular foreign body (e.g. metal shavings) unless removed
    6. Other implanted medical devices: (e.g. Swan Ganz catheter)
    7. Insulin pump
    8. Retained metal shrapnel or bullet
    E.5 End points
    E.5.1Primary end point(s)
    The co-primary endpoint will be measured using serial biomarkers of renal and myocardial injury in all patients in the trial.

    E.5.1.1Timepoint(s) of evaluation of this end point
    1. Kidney: Serum creatinine measured at baseline, on return to ITU, and at 6-12, 24, 48, 72, 96 hours, 6 weeks and 3 months postoperatively.
    2. Myocardium: Serum troponin measured at baseline, on return to ITU, and at 6-12, 24, 48 and 72 hours postoperatively
    E.5.2Secondary end point(s)
    - Adverse events, other than those included in the primary and secondary endpoints.
    - Post-surgery organ injury assessed by SOFA scores at baseline, pre-assessment, surgery and 24, 48, 72 and 96 hours post-surgery.
    - Sepsis-related Organ Failure Assessment Score pre-surgery, and at 24, 48, 72 and 96 hours post-surgery.
    - Urinary AKI biomarkers pre-surgery, and at 6-12 and 24 post-surgery.
    - Absolute change from baseline for serum creatinine.
    - Serum creatinine and eGFR at 6 weeks post-surgery using the Modification of Diet in Renal Disease equation.
    - Lung Injury; Arterial alveolar oxygen ratios immediately pre-surgery, and at 24, 48, 72 and 96 hours post-surgery.
    - GI Tract Injury: Serum amylase and liver function tests immediately pre-surgery, and at 24, 48, 72 and 96 hours post-surgery.
    - Hospital stay and cumulative resource use: time until extubation, discharge from HDU and discharge from hospital will all be measured from the start of surgery; deaths will be censored at time of death
    - The following clinical adverse events will be recorded:
    - Sepsis will be defined as suspected or documented infection and an acute change in total SOFA score ≥2 points consequent to the infection.2 For the purposes of the study suspected or documented infection will be defined as the commencement of intravenous antibiotics. The rise in SOFA score will be assessed within 72 hours of the commencement of antibiotics.
    - Peak lactate within 24 hours of surgery and time to resolution of hyperlactataemia (arterial serum lactate >2.5 mmol/L) post peak.
    - Acute Kidney Injury defined as KDIGO stage 1, 2 or 3.3
    - Acute lung injury, defined as per the Berlin ARDS guidance.4
    - Low cardiac output, defined as new intra-or postoperative intra-aortic balloon pump insertion or a cardiac index of <2.2 L/min/ m2 refractory to appropriate intravascular volume expansion after correction or attempted correction of any dysrhythmias, or the administration of the inotropes Enoximone, Milrinone or Levosimendan.
    - Stroke; diagnosed by brain imaging (CT or MRI), in association with new onset focal or generalized neurological deficit (defined as deficit in motor, sensory or co-ordination functions).
    - Acute liver injury will be defined as an acute derangement of liver enzymes three times the upper limit of normal, or a serum amylase concentration >1000 ng/ml.
    - Acute intestinal injury will be defined a radiological, operative or post-mortem evidence of gut ischaemia.
    - A composite endpoint of all of the above: Any organ injury, sepsis or death.
    Endothelial function as measured by the reactive hyperemia peripheral arterial tonometry (RH-PAT) index.
    E.5.2.1Timepoint(s) of evaluation of this end point
    As above
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States No
    E.8.5.1Number of sites anticipated in the EEA1
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The definition of the end of the trial as a whole is when database lock has occurred.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months3
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 40
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 82
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state122
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 122
    F.4.2.2In the whole clinical trial 122
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    The treatment or other interventions will not continue once the research has finished.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-08-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-08-23
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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