Clinical trial NCT03825250: The Val-CARD Trial
Official title: A Randomised Controlled Trial of Pre-surgery Sodium ValpRoate, for the Prevention of Organ Injury in Cardiac Surgery: THE Val-CARD TRIAL
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Cardiac Valve Disease
Coronary Artery Disease
Organ Failure, Multiple
Keywords: Sodium Valproate
Cardiac Surgery
Organ Injury Prevention
Lead sponsor: University of Leicester
Sponsor class: OTHER
First posted: 2019-01-31
Enrollment: 122
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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

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.

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.

Eligibility 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.

Primary outcomes:
measure: Change of Serum Creatinine level
timeFrame: Baseline, 2 weeks, 4 weeks, 0-6, 6-12, 24, 48, 72, and 96 hours post-operatively
measure: Change of Serum Troponin I level
timeFrame: Baseline, at 0-6, 6-12, 24, 48 and 72 hours post-operatively
Secondary outcomes:
measure: Change in Multiple organ dysfunction - Sepsis-related Organ Failure Assessment (SOFA) Score)
timeFrame: Baseline, 4 weeks, 0-6, 24, 48, 72 and 96 hours
measure: NGAL (Neutrophil gelatinase associated lipocalcin)
timeFrame: Baseline, day before surgery, 6-12, 24 and 48 hours post-surgery.
measure: Lung Injury - Arterial alveolar oxygen (PaO2/FiO2) ratios
timeFrame: Baseline, day before surgery, 24, 48, 72 and 96 hours post-surgery.
measure: AST (Aspartate Transaminase)
timeFrame: Baseline, day before surgery, 0-6, 6-12, 24, 48, 72 and 96 hours post-surgery
measure: ALT (Alanine Transaminase)
timeFrame: Baseline, day before surgery, 0-6, 6-12, 24, 48, 72 and 96 hours post-surgery
measure: Bilirubin
timeFrame: Baseline, day before surgery, 0-6, 6-12, 24, 48, 72 and 96 hours post-surgery
measure: Alkaline Phosphatase
timeFrame: Baseline, day before surgery, 0-6, 6-12, 24, 48, 72 and 96 hours post-surgery
measure: Serum Amylase
timeFrame: Baseline, day before surgery, 0-6, 6-12, 24, 48, 72 and 96 hours post-surgery
measure: Assessment of resource use - Time until extubation
timeFrame: Time (hours) measured from the start of surgery - to extubation (up to 30 days)
measure: Length of stay in Intensive Care Unit
timeFrame: Time (hours) measured from the start of surgery to discharge from ICU (up to 30 days)
measure: Length of Stay in Hospital
timeFrame: Time (days) measured from the start of surgery to discharge from hospital (up to 90 days)
measure: Sepsis
timeFrame: Baseline, 4 weeks before surgery, 0-6, 6-12, 24, 48, 72 and 96 hours post-surgery
measure: Rate of mortality
timeFrame: Within 30-days from surgery and at 1 year from surgery
measure: Bleeding and Transfusion
timeFrame: Intra-operative and between time of surgery and hospital discharge up to two weeks
measure: Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
timeFrame: Post-operative up to 3 months follow-up from time of surgery
measure: Mechanism study: Mithocondrial function of microvessels from tissue biopsies
timeFrame: At time of surgery
measure: Mechanism study: microRNAs isolation from microvessels
timeFrame: At time of surgery
measure: Mechanism study: Chromatin Immunoprecipitation (ChIP) of microvessels from tissue biopsies
timeFrame: At time of surgery
measure: Mechanism study: Mithocondrial function measured in right atrium myocardium tissue biopsies
timeFrame: At time of surgery
measure: Mechanism study: microRNA isolation from right atrium myocardium tissue biopsies
timeFrame: At time of surgery
measure: Mechanism study: Chromatin Immunoprecipitation (ChIP) in right atrium myocardium tissue biopsies
timeFrame: At time of surgery
measure: Mechanism study: Mithocondrial function measured in adipose tissue biopsies
timeFrame: At time of surgery
measure: Mechanism study: microRNA isolation in adipose tissue biopsies
timeFrame: At time of surgery
measure: Mechanism study: Chromatin Immunoprecipitation (ChIP) in adipose tissue biopsies
timeFrame: At time of surgery
measure: Mechanism study: Measurement of microvesicles in urine samples
timeFrame: 1 day before surgery, 12 and 24 hours following surgery
measure: Mechanism study: Measurement of microRNAs in urine samples
timeFrame: 1 day before surgery, 12 and 24 hours following surgery
measure: Mechanism study: Measurement of histone acetylation in urine samples
timeFrame: 1 day before surgery, 12 and 24 hours following surgery
measure: Mechanism study: Measurement of gene expression in urine samples
timeFrame: 1 day before surgery, 12 and 24 hours following surgery
measure: Mechanism study: Cardiac Magnetic Resonance Imaging - Cardiac Function
timeFrame: Baseline, 1 day before surgery and 3 months following surgery
measure: Mechanism study: Cardiac Magnetic Resonance Imaging - Cardiac adiposity content
timeFrame: Baseline, 1 day before surgery and 3 months following surgery
measure: Mechanism study: Cardiac Magnetic Resonance Imaging - Visceral adiposity content
timeFrame: Baseline, 1 day before surgery and 3 months following surgery
Other outcomes:
Locations:
city: Leicester
country: United Kingdom
facility: Glenfield Hospital
state: Leicestershire
Study officials:
affiliation: BHF Professor of Cardiac Surgery, University of Leicester
name: Gavin Murphy, MD
role: STUDY_CHAIR
affiliation: Academic Clinical Lecturer in Cardiac Surgery, University of Leicester
name: Marius Roman, MD
role: PRINCIPAL_INVESTIGATOR
References: