Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623001032640
Ethics application status
Approved
Date submitted
12/07/2023
Date registered
22/09/2023
Date last updated
22/09/2023
Date data sharing statement initially provided
22/09/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
The ALLEVIATE study. A prospective observational comparative plasma and cerebrospinal fluid pharmacokinetics study of levetiracetam in aneurysmal subarachnoid haemorrhage and traumatic brain injury.
Scientific title
The ALLEVIATE study. A prospective observational comparative plasma and cerebrospinal fluid pharmacokinetics study of levetiracetam in aneurysmal subarachnoid haemorrhage and traumatic brain injury.
Secondary ID [1] 310052 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
traumatic brain injury 330590 0
aneurysmal subarachnoid haemorrhage 330591 0
Condition category
Condition code
Neurological 327425 327425 0 0
Other neurological disorders
Injuries and Accidents 327577 327577 0 0
Other injuries and accidents

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
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.
Intervention code [1] 326462 0
Not applicable
Comparator / control treatment
There is no control group, as both cohorts of sTBI and aSAH patients will be receiving standard care.
Control group
Active

Outcomes
Primary outcome [1] 335289 0
The primary outcome will be the pharmacokinetic endpoints of levetiracetam at steady state concentration in plasma and CSF. The following parameters will be assessed:
-Mean area under the concentration time curve (AUC)
-Mean maximum concentration (Cmax)
-Mean minimum concentration (Cmin)
-Mean volume of distribution (Vd)
-Mean elimination rate constant
Urine from an indwelling catheter will be collected during the dosing interval to assess the urinary drug clearance.
These endpoints will be reported in each of the two neurocritical groups of sTBI and aSAH.
Timepoint [1] 335289 0
For Levetiracetam administered via the Intravenous route, blood and CSF samples will be collected at the following times during the dosing interval: -30 minutes to 0 minutes (pre-dose), + 15 minutes (end of levetiracetam infusion), 60 minutes (1 hour post dose), 90 minutes (1.5 hours post dose), 180 minutes (3 hours post dose), 360 minutes (6 hours post dose), 480-720 minutes (8-12 hours post dose).
For Levetiracetam administered via the oral/nasogastric route, blood and CSF samples will be collected at the following times during the dosing interval: -30 minutes to 0 minutes (pre-dose), + 30 minutes (after oral administration), 60 minutes (1 hour post dose), 90 minutes (1.5 hours post dose), 180 minutes (3 hours post dose), 360 minutes (6 hours post dose), 480-720 minutes (8-12 hours post dose).
The total volume of urine produced over the duration of the sampling period will be collected for a urinary creatinine clearance measurement. A 1mL aliquot taken from the total volume of urine collected will be kept to assess the urinary drug clearance over the dosing interval.
Secondary outcome [1] 423784 0
A Likert scale questionnaire will be used to evaluate feasibility relating to prolonged portable EEG monitoring in the ICU, recording quality and the duration of recording. The outcome measure will be the percentage of recruited patients that have the EEG performed and completed as per the protocol.
Timepoint [1] 423784 0
The EEG recording will be undertaken in the ICU on the day of sampling to study the brain's electrical activity and evaluate seizures. EEG recording will commence prior to administration of levetiracetam and will continue for the duration of one dosing interval.

Eligibility
Key inclusion criteria
Patients treated in the ICU are eligible for inclusion in the study if ALL of the following criteria are met:
Group 1: Severe blunt TBI with Glasgow Coma Score (GCS) of less than or equal to 8 on admission OR GCS greater than 8 on admission AND the presence of computed tomographic imaging consistent with severe TBI including subdural haemorrhage, epidural haemorrhage, intra-cerebral haemorrhage, or diffuse axonal injury (n=20)
OR
Group 2: aneurysmal SAH confirmed via computed tomographic imaging (n=20)

AND
• Age >/= 18 years
• Planned administration of oral or intravenous levetiracetam for seizure treatment/prophylaxis
• Arterial line in situ or planned insertion
• External-ventricular drain (EVD) in situ or planned insertion
• In-dwelling urinary catheter in situ or planned insertion
• Informed consent has been obtained from the patient or the Person Responsible
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients are excluded from the study if ONE OR MORE of the following criteria are met:
• Known or suspected hypersensitivity to levetiracetam or piracetam
• Devastating brain injury with expected or confirmed brain death within 48 hours of ICU admission
• Receiving extra-corporeal membrane oxygenation
• Receiving renal replacement therapy
• Acute Liver failure or Child-Pugh C liver cirrhosis
• Pregnant patients or lactating mothers

Study design
Purpose
Natural history
Duration
Cross-sectional
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
Population PK model build
Pmetrics version 1.5.2 (a package for R®) will be used to develop a population PK model based on the non-parametric adaptive grid algorithm. A systematic model building approach will be completed to determine the structural base model for each population group. One-, two- and three- compartment PK models will be tested using the Nonparametric Adaptive Grid algorithm within Pmetrics® package for R®. Where necessary, absorption and bioavailability will be estimated. Both Lambda (additive) and Gamma (multiplicative) error models will be tested for inclusion. Biologically-plausible variables tested will be actual body weight, BMI, age, serum creatinine, CrCL, Acute Physiology and Chronic Health Evaluation II (APACHE II) and Sequential Organ Failure Assessment (SOFA) scores. If the inclusion of a variable resulted in an increase in the coefficient of determination of the linear regression (R2) and in a reduction of the bias of the goodness-of-fit plots as well as a statistically significant reduction in the log-likelihood (P < 0.05), the covariate was supported for inclusion.
Population pharmacokinetic model diagnostics
The R2 and the bias of the observed versus predicted plots as well as the log-likelihood of each run will be considered for the goodness-of-fit evaluation. Predictive performance evaluation will be based on mean predicted error (bias) and the mean bias-adjusted prediction error (imprecision) of the population and individual prediction models. The visual predictive check plot and the normalised prediction distribution errors were used to test the suitability of the final covariate models.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
25/09/2023
Actual
Date of last participant enrolment
Anticipated
29/09/2025
Actual
Date of last data collection
Anticipated
24/11/2025
Actual
Sample size
Target
40
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 25129 0
Royal Brisbane & Womens Hospital - Herston
Recruitment postcode(s) [1] 40796 0
4029 - Herston

Funding & Sponsors
Funding source category [1] 314218 0
Charities/Societies/Foundations
Name [1] 314218 0
Royal Brisbane and Women's Hospital & RBWH Foundation Project Grant
Country [1] 314218 0
Australia
Primary sponsor type
University
Name
The University of Queensland
Address
University of Queensland Centre for Clinical Research (UQCCR)Building 71/918Royal Brisbane and Women's Hospital (RBWH)Herston QLD 4006
Country
Australia
Secondary sponsor category [1] 316152 0
None
Name [1] 316152 0
Address [1] 316152 0
Country [1] 316152 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 313342 0
Metro North Human Research Ethics Committee A
Ethics committee address [1] 313342 0
Metro North Office of ResearchLevel 7, Block 7RBWH Campus1 Butterfield StHerston QLD4029
Ethics committee country [1] 313342 0
Australia
Date submitted for ethics approval [1] 313342 0
30/01/2023
Approval date [1] 313342 0
04/04/2023
Ethics approval number [1] 313342 0
92516

Summary
Brief summary
The ALLEVIATE study aims to determine what level of levetiracetam concentrations are achieved in the blood and brain, in ICU patients with bleeding in the brain due to severe traumatic brain injuries or ruptured aneurysms. Although research suggests that there needs to be a certain amount of levetiracetam in the blood to stop or prevent seizures, it is currently unclear, whether the amount in the blood results in the right level in the brain (the site of injury). The purpose of this study is to determine how best to dose levetiracetam so that adequate levels are achieved in the brain in patients at high risk of seizures. We hypothesise that there may be significant differences in levetiracetam brain fluid concentrations between the two groups of patients.
Patients who are receiving Levetiracetam for the treatment or prevention of seizures as part of their standard care for bleeding in the brain will be considered for participation. Participation will involve sampling of blood and brain fluid over one dosing interval on one day only, to measure the concentration of levetiracetam. Blood samples will be collected from an existing arterial line. The brain fluid is collected from an external ventricular drain that is already in place as part of usual care to relieve pressure in the brain. A prolonged electroencephalogram (EEG) recording will be undertaken prior to administration of levetiracetam dose and continuing until the next dose on the day of sampling. EEG is a non-invasive procedure that studies the brain’ electrical activity and is used to evaluate seizures.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 127806 0
A/Prof Dr Jayesh Dhanani
Address 127806 0
Intensive Care Administrative Office Level 3 Ned Hanlon BuildingRoyal Brisbane and Women's Hospital Butterfield St Herston QLD 4006
Country 127806 0
Australia
Phone 127806 0
+61 7 3646 8897
Fax 127806 0
Email 127806 0
jayesh.dhanani@health.qld.gov.au
Contact person for public queries
Name 127807 0
Ms Cheryl Fourie
Address 127807 0
Intensive Care ResearchLevel 3 Ned Hanlon BuildingRoyal Brisbane and Women's HospitalButterfield StHerston QLD 4006
Country 127807 0
Australia
Phone 127807 0
+61 7 3646 8897
Fax 127807 0
Email 127807 0
cheryl.fourie@health.qld.gov.au
Contact person for scientific queries
Name 127808 0
A/Prof Dr Jayesh Dhanani
Address 127808 0
Intensive Care Administrative Office Level 3 Ned Hanlon BuildingRoyal Brisbane and Women's Hospital Butterfield St Herston QLD 4006
Country 127808 0
Australia
Phone 127808 0
+61 7 3646 8897
Fax 127808 0
Email 127808 0
jayesh.dhanani@health.qld.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.