An observational study in Brain Injuries, Traumatic, Brain Injuries, Acute and Hypoxia, Brain, sponsored by University of Pecs. Recruiting at 4 sites in Hungary. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2026-09-29.
Sponsored by University of Pecs · Observational
Traumatic brain injury (TBI) and other conditions that reduce blood flow to the brain - such as cardiac arrest (CA) - are life-threatening medical emergencies. When brain cells are damaged, they release specific proteins into the bloodstream. These proteins, called neurobiomarkers, can be measured in blood samples and may help doctors assess the severity of brain injury, guide treatment, and predict patient outcomes.
A major gap in current knowledge is how these neurobiomarkers behave during the very first minutes and hours after injury - the so-called "hyperacute" phase - especially when patients are still being treated by paramedics or have just arrived at the emergency department (ED). It is not yet clear whether biomarker levels rise immediately at the moment of injury or gradually over time, and how quickly they can be reliably detected.
The CHARON study investigates the time-dependent kinetics of key neurobiomarkers - including S100B, glial fibrillary acidic protein (GFAP), neuron-specific enolase (NSE), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), neurofilament light chain (NFL), and Tau proteins- during the hyperacute phase of acute brain injury. In addition to these proteins, microRNAs, polar metabolites, and lipid metabolites are also examined as potential biomarkers.
The study enrolls three groups of participants:
Serial blood samples are collected at multiple time points, beginning during prehospital care and continuing through the first 24 hours of hospital admission. No experimental treatments are given - all participants receive standard medical care.
By analyzing biomarker concentration and kinetics across all three groups and correlating findings with neurological outcome at 30 days, the investigators aim to identify the most clinically effective neurobiomarkers for early diagnosis and prognosis of acute brain injury.
The study is a prospective multi-center investigation conducted at emergency departments, intensive care units, and ambulance services across Hungary.
Background
Traumatic brain injury (TBI) and cardiac arrest (CA) are among the leading causes of mortality and long-term disability worldwide. Together, these conditions affect an estimated 60 million people globally each year. TBI alone accounts for 27-69 million new cases annually, while out-of-hospital cardiac arrest affects approximately 275,000 individuals per year in Europe. Both conditions share a common pathobiological pathway: acute cerebral hypoxia and hypoperfusion trigger proteolysis-associated systemic cascades among others an inflammatory response in central nervous system (CNS), resulting in the release of neuronal and glial injury markers - including S100 calcium-binding protein B (S100B), neuron-specific enolase (NSE), glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) - into the systemic circulation.
Six blood-based protein neurobiomarkers have been extensively studied in acute brain injury: S100B and GFAP - indicators of astroglial damage; neuron-NSE and UCH-L1 - reflecting neuronal cell body injury; neurofilament light chain (NFL) - associated with axonal damage; and Tau - signaling post-injury neurodegeneration. Beyond these proteins, microRNAs (particularly miR-124), polar metabolites, and lipid metabolites (lysophosphatidylcholines, ether phosphatidylcholines, and sphingomyelins) are also under investigation as potential biomarkers of acute brain injury.
A critical and unresolved challenge is the behavior of these biomarkers during the hyperacute phase - the first minutes to hours following injury - particularly in prehospital and emergency settings. It remains unclear whether biomarker release is instantaneous at the moment of impact or gradual and continuous over time. Serial sampling studies are scarce (especially the hyperacute prehospital phase), and significant uncertainty exists regarding the influence of secondary injuries, extracranial trauma, prehospital interventions, and hemodilution on biomarker kinetics.
Sample Collection and Processing Arterial or venous blood samples are collected at study arm-specific time points detailed below. At each time point, two blood samples are collected: one serum gel tube (8 ml) and one ethylenediaminetetraacetic acid (EDTA) plasma tube (3.5 ml). Serum tubes are allowed to coagulate at ambient temperature for 45 ± 15 minutes prior to centrifugation. EDTA plasma tubes are kept on ice immediately after collection and centrifuged as soon as possible. Both tube types are centrifuged at 1,500g (4,000 rpm) for 10 minutes. Both tube types must be centrifuged within 120 minutes after sample collection. Following centrifugation, 5 × 0.5 ml serum and 4 × 0.5 ml plasma aliquoted to labelled cryovials and stored at -80°C (temporary storage at -20°C is acceptable). In Arm 1, an additional 2.7 mL 3.2% sodium-citrate tube is collected at the first prehospital contact for point-of-care rotational thromboelastometry (ClotPro®); Citrated whole blood samples for ClotPro® rotational thromboelastometry analysis are maintained at ambient temperature and analysed on-site.
Arm 1 - Prehospital TBI/Polytrauma:
Prehospital phase:
Sample 1: immediately after intravenous access is secured Sample 2: immediately before transport initiation
In-hospital phase:
Sample 3: upon emergency department admission Sample 4: 1 hour after ED admission Sample 5: 6 hours after ED admission Sample 6: 24 hours after ED admission
Arm 2 - Prehospital Cardiac Arrest:
Prehospital phase:
Sample 1: immediately after the first adrenaline dose (asystole/pulseless electrical activity [PEA]) or first defibrillation (ventricular fibrillation [VF]/ pulseless ventricular tachycardia [pVT]) Sample 2: at 20 minutes of ongoing resuscitation Sample 3: immediately after ROSC or prior to declaration of death
In-hospital phase:
Sample 4: upon emergency department admission Sample 5: 1 hour after ED admission Sample 6: 6 hours after ED admission Sample 7: 24 hours after ED admission
Arm 3 - In-hospital TBI:
Sample 1: upon emergency department admission Sample 2: 1 hour after ED admission Sample 3: 6 hours after ED admission Sample 4: 24 hours after ED admission
Biomarker Measurements S100B and NSE: Electrochemiluminescence immunoassay (ECLIA; Elecsys S100 and Elecsys NSE assays) on the Cobas 8000 modular analyzer (Roche Diagnostics, Mannheim, Germany) at the Department of Laboratory Medicine, University of Pécs.
Brain-derived Tau (BD-Tau) and phosphorylated Tau-217 (p-Tau-217): Immunoassay on the Beckman Coulter DXi 9000 analyzer at the Department of Laboratory Medicine, University of Pécs.
GFAP and UCH-L1: VIDAS® TBI assay on the VIDAS®3 instrument (bioMérieux SA., Marcy-l'Étoile, France) at Örebro University, Sweden.
NFL, Tau, ionized calcium-binding adaptor molecule 1 (IBA-1), IL-1β, IL-6, TNF-α: Commercially available ELISA kits using the BMG LabTech CLARIOstar multimode microplate reader (BMG Labtech GmbH, Ortenberg, Germany) at the Szentágothai Research Centre, University of Pécs.
Metabolomics and lipidomics: Polar metabolites detected via Agilent 7890B GC coupled with a 7200 Q-TOF MS; lipids quantified by ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-QTOFMS) at Örebro University, Sweden.
MicroRNA: Cell-free total RNA isolated from 500 µl serum using the miRNeasy serum/plasma kit (Qiagen, Hilden, Germany). RNA integrity confirmed by NanoDrop 2000. Reverse transcription performed using the miRCury LNA Universal RT microRNA PCR Kit (Qiagen). Droplet digital PCR (ddPCR) targeting miR-30a, miR-487b, let-7b, miR-363, and miR-126 performed at the Department of Laboratory Medicine, University of Pécs.
Cytokine and chemokine profiling: Simultaneous detection of multiple inflammatory mediators using the Human Cytokine Array (ARY022B, R\&D Systems, Minneapolis, MN, USA). Chemiluminescent signals are captured at multiple exposure times for optimal detection.
Rotational thromboelastometry is performed on citrated whole blood samples (sodium citrate 3.2%) using the ClotPro® analyser (Haemonetics Corporation, Boston, MA, USA). Three assays are used: the EX-test (extrinsic pathway activation with recombinant tissue factor), the IN-test (intrinsic pathway activation with ellagic acid), and the FIB-test (EX-test with the platelet inhibitor cytochalasin D, isolating the fibrinogen contribution to clot firmness). The analysis is performed at the ambulance base stations and at the participating hospitals.
Statistical Analysis
Statistical significance threshold: p \< 0.05. Given the expected non-normal distribution of biomarker data, non-parametric methods are applied as primary statistical tests, including the Mann-Whitney U test and the Kruskal-Wallis test. Diagnostic and prognostic performance is evaluated using receiver operating characteristic (ROC) curve analysis with area under the curve (AUC); AUC comparisons are performed using the DeLong test. The association with mortality and neurological outcome is examined by binary logistic regression (univariable and multivariable, with pre-defined covariates).
Sample size was determined by power analysis for binary logistic regression - the most statistically demanding analysis - using a medium effect size (Cohen's d = 0.5), α = 0.05, and a power of 0.80. A Mann-Whitney equivalent correction of +10% was applied to account for non-normality of biomarker distributions. This yields a required sample size of 159 participants per arm, for a total target enrollment of 477 participants across all three arms. No single center may contribute more than 40% of the total sample to mitigate center effects. All analyses will be performed using R software (RStudio environment), with a biostatistician involved throughout.
1,721 studies on the registry are indexed under Brain Injuries, Traumatic; 447 are open to participants now.
This study's planned enrollment of 477 is above the median of 117 across 557 observational studies indexed under Brain Injuries, Traumatic.
Browse Brain Injuries, Traumatic studies →University of Pecs is the lead sponsor of 106 studies on the registry; 25 are open to participants now.
Counted across the registry records on this site, refreshed daily.
Adults aged 18 years or older presenting to emergency departments or prehospital emergency services in Hungary with acute brain injury (traumatic brain injury or cardiac arrest). Participants are enrolled consecutively at emergency departments, intensive care units, and by the Hungarian National Ambulance Service across multiple regions of Hungary.
Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Exclusion Criteria (all arms)
Serial blood samples are collected from severely injured traumatic brain injury and/or polytrauma patients (ISS \>16 and/or GCS \<9) categorized as T1 triage in the prehospital setting. Sampling occurs at two prehospital time points (immediately after intravenous access is secured; immediately before transport initiation) and at four in-hospital time points (upon emergency department admission; 1, 6, and 24 hours after ED admission). No experimental intervention is administered; participants receive standard emergency care.
Serial blood samples are collected from cardiac arrest patients managed in the prehospital setting. Sampling occurs at three prehospital time points (after the first adrenaline dose or defibrillation; at 20 minutes of ongoing resuscitation; at return of spontaneous circulation or prior to declaration of death) and at four in-hospital time points (upon emergency department admission; 1, 6, and 24 hours after ED admission). No experimental intervention is administered; participants receive standard resuscitation care.
Serial blood samples are collected from severe TBI patients (ISS \>16 and/or GCS \<9) enrolled upon emergency department admission. Sampling occurs at four time points: upon ED admission and at 1, 6, and 24 hours after admission. No experimental intervention is administered; participants receive standard emergency and intensive care.
Prehospital Mortality
Death occurring prior to emergency department arrival, assessed in prehospital-enrolled participants.
Time frame: Day 1 (Up to 24 hours from enrollment)
In-hospital Mortality
Death occurring during the hospital stay, assessed in all study arms.
Time frame: Up to 30 days
Prehospital Neurological Status
Glasgow Coma Scale (GCS) score documented by the first-responding paramedic at the scene, prior to sedation or intubation. The GCS ranges from 3 (deep unconsciousness) to 15 (fully alert); higher scores indicate better neurological status.
Time frame: Baseline (At first prehospital contact)
Abbreviated Injury Scale Score Assessment
The Abbreviated Injury Scale (AIS) categorizes injuries by body region on a scale from 1 (minor) to 6 (unsurvivable); higher scores indicate greater injury severity. Calculated based on clinical and imaging parameters at emergency department admission.
Time frame: [Time Frame: Day 1 (Up to 24 hours from enrollment)]
Injury Severity Score Assessment
The Injury Severity Score (ISS) is an anatomical scoring system ranging from 0 to 75; higher scores indicate greater overall injury severity. The ISS is calculated from Abbreviated Injury Scale (AIS) scores, using clinical and imaging parameters assessed upon emergency department admission.
Time frame: [Time Frame: Day 1 (Up to 24 hours from enrollment)]
Severity of Intracranial Pathology on Admission CT - Marshall Classification
Categories range from I (no visible intracranial pathology) to VI (diffuse injury with mass lesion); higher categories indicate greater severity of intracranial injury.
Time frame: [Time Frame: Day 1 (Up to 24 hours from enrollment)]
Severity of Intracranial Pathology on Admission CT - Rotterdam CT Score
Initial head CT scan scored according to the Rotterdam CT Score. The score ranges from 1 to 6; higher scores indicate greater severity of intracranial injury and worse predicted outcome.
Time frame: [Time Frame: Day 1 (Up to 24 hours from enrollment)]
30-day Neurological Outcome in Cardiac Arrest Patients
Neurological outcome at 30 days assessed by the Cerebral Performance Scale (CPC) in cardiac arrest patients (Arm 2). The CPC ranges from 1 (good cerebral performance) to 5 (brain death); higher scores indicate worse neurological outcome.
Time frame: 30 days after cardiac arrest
30-day Functional Outcome in Traumatic Brain Injury Patients
Functional outcome assessed by the Glasgow Outcome Scale Extended (GOS-E) in traumatic brain injury patients (Arms 1 and 3). The GOS-E ranges from 1 (death) to 8 (upper good recovery); higher scores indicate better functional outcome.
Time frame: 30 days after injury
Need for Neurosurgical Intervention
Occurrence of neurosurgical intervention (e.g., craniotomy, decompressive craniectomy, intracranial pressure monitoring) within 72 hours of injury.
Time frame: Within 72 hours of emergency department admission
Resuscitation Characteristics in Cardiac Arrest
No-flow time (interval without CPR) and low-flow time (duration of BLS and ALS) and their association with prehospital, 6-hour, 24-hour, and 72-hour mortality.
Time frame: Up to 72 hours after cardiac arrest
Long-term neurological and functional outcome
Neurological outcome assessed using the Glasgow Outcome Scale - Extended (GOS-E) in traumatic brain injury patients (Arms 1 and 3) The GOS-E ranges from 1 (death) to 8 (upper good recovery); higher scores indicate better functional outcome and the Cerebral Performance Scale (CPC) in cardiac arrest patients (Arm 2) the CPC ranges from 1 (good cerebral performance) to 5 (brain death); higher scores indicate worse neurological outcome. Functional outcome assessed using the modifed Rankin Scale (mRS) in all arms. Assessments performed by structured telephone interview or in-person evaluation by trained research personel.
Time frame: 6 months and 12 months after injury or cardiac arrest
Plan to share: Undecided
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