The ALLEVIATE study. A prospective observational comparative plasma and cerebrospinal fluid pharmacokinetics study of levetiracetam in aneurysmal subarachnoid haemorrhage and traumatic brain injury.

This is a prospective, single site, open label, observational, population pharmacokinetic (PK) study of levetiracetam in aneurysmal subarachnoid haemorrhage (aSAH) and traumatic brain injury (sTBI). A patient who is receiving levetiracetam for the treatment or prevention of seizures as part of standard care, who meets all of the inclusion and none of the exclusion criteria, will be considered for participation. After a minimum of three doses of levetiracetam; up to seven samples of blood (plasma) and up to seven samples of cerebrospinal fluid (CSF) will be collected over one dosing interval on one day only, as per the sampling schedule. Levetiracetam dose and dosing interval will be determined by the treating team in accordance with standard prescribing procedures. Levetiracetam for prophylaxis is typically prescribed 1000mg - 3000mg per day with twice daily dosing. Levetiracetam for treatment may be prescribed 1000mg- up to 6000mg per day with twice or three times a day dosing. Oral/nasogastric dosing of levetiracetam is equivalent to Intravenous dosing. Sampling will take place on one day only. Blood samples will be drawn from a pre-existing arterial line or central venous catheter that is placed as part of routine care in the Intensive Care. Blood samples will be drawn into fluoride oxalate tubes at pre-specified timepoints (up to 7 times). No more than 35mLs of blood will be collected for study purposes. The sampling will be performed in an aseptic manner by experienced research nurses. Cerebral spinal fluid samples will be collected at the same time as plasma (provided that there is CSF that has collected passively in the external ventricular drainage chamber at that timepoint). CSF will be collected into fluoride oxalate tubes from an external ventricular drain that is already in-situ as part of care for the patient's condition. The CSF samples will be collected under sterile technique by experienced research nurses as per work unit guidelines. Biospecimen sampling will align with routine collection as part of standard care where possible. The total urine volume over the duration of one dosing interval on the day of sampling will be collected for a urinary creatinine clearance measurement. This will be analysed by the pathology laboratory local to the ICU in line with standard procedures. Before the volume of urine is sent to the pathology laboratory, a 1mL aliquot will be kept to determine the renal excretion of levetiracetam. Electroencephalograph (EEG) recording will be performed on one day only, for the duration of the sampling period, to study the brain's electrical activity and evaluate the presence of seizures. The EEG is performed in ICU by trained certified neurophysiology scientists who will ensure the test is performed according to international standards. EEG parameters for analysis will include assessment of the background rhythm; presence of epileptiform activity; and/or presence of electrographic seizures. The sample size for the study is at least 20 participants each for sTBI and aSAH to allow for comparison between the two neurocritical care groups. Sample assay for the study drug will be performed in the University of Queensland Centre for Clinical Research bioanalysis laboratory. PK analyses will be performed and statistical comparisons made between the two diagnoses groups. The total duration of the study is approximately 36 months to allow for recruitment of target sample size, data entry, analysis and reporting of results. As this is an observational study and there is no follow up, the overall duration of participation will be from the time of enrolment and up to 24 hours post the sampling period. As this is a single site study, protocol adherence will be easily monitored. The study will be conducted in accordance with ethical principles consistent with the Declaration of Helsinki, and all relevant national and local guidelines on the ethical conduct of research. The research team will include experienced research coordinators and intensive care specialists all with GCP training. Although potentially more frequent than standard care, all the study procedures are routinely performed within the intensive care environment and will be performed by experienced nursing staff.