BLOOD BIOMARKERS TO IMPROVE MANAGEMENT OF MILD TRAUMATIC BRAIN INJURY IMPLIMENTACIÓN STUDY
Conditions: Mild Traumatic Brain Injury (mTBI)
Sponsor: Hospital Universitario 12 de Octubre

       
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Protocol BRAINI2-IMPLEMENTATION STUDY 
Registration No.: No. 
Ref: TP25/0144 
 Blood Biomarkers to improve management of mild traumatic BRAIN Injury 
implementation study 
National Coordinating Investigator:  Prof. Alfonso Lagares 
Department of Neurosurgery, Head 
Hospital Universitario 12 de Octubre, 
Avda de Córdoba s/n, 28041 Madrid, Spain 
Tel:+34 913908282 - e-mail: alfonlag@ucm.es 
 
BRAINI2-Elderly Coordinating Investigator:  Prof. Alfonso Lagares 
Department of Neurosurgery, Head 
Hospital Universitario 12 de Octubre, 
Avda de Córdoba s/n, 28041 Madrid, Spain 
Tel:+34 913908282 - e-mail: alfonlag@ucm.es 
 
Methodology expert: Dr Javier de la Cruz 
Instituto de Investigación imas12 
Hospital Universitario 12 de Octubre 
Avda de Córdoba s/n 28041 Madrid, Spain 
Tel: +34 917792648 - E-mail: jdlcruz@h12o.es 
 
Sponsor:   
Fundación Investigación Biomédica Hospital 12 de Octubre (FIBH12O) 
 
This work is supported by EIT-Health funding. 
 
 
 
 
 

       
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1. 
STUDY SUMMARY 
4 
2. 
RATIONALE FOR THE STUDY 
7 
2.1. 
BACKGROUND AND CURRENT MANAGEMENT 
7 
2.2. 
BLOOD BIOMARKERS IN MTBI 
8 
2.3. 
VIDAS TBI 
8 
3. 
STUDY OBJECTIVES AND OUTCOME MEASURES 
9 
3.1. 
GENERAL OBJECTIVE 
9 
3.2. 
PRIMARY OBJECTIVE AND OUTCOME MEASURE 
9 
3.3. 
SECONDARY OBJECTIVES AND OUTCOME MEASURES 
10 
4. 
STUDY DESIGN 
10 
4.1. 
STUDY OVERVIEW AND STUDY POPULATION 
10 
5. 
BRAINI2-IMPLEMENTATION PROCEDURE 
11 
5.1. 
STUDY ENROLLMENT METHOD AND FEASIBILITY 
11 
5.2. 
STUDY TIMELINE AND PLANNED MANAGEMENT ALGORITHM 
12 
5.3. 
PARAMETER ASSESSMENTS 
13 
5.3.1. 
Clinical parameters 
13 
5.3.2. 
Biological assessments (BA) 
14 
5.3.3. 
DATA COLLECTION AND DATA MONITORING 
14 
5.3.4. 
CT SCAN ANALYSIS 
15 
6. 
STUDY STOPPING RULES 
16 
6.1. 
STUDY STOPPING CRITERIA FOR A PARTICIPATING SUBJECT 
16 
7. 
STATISTICAL CONSIDERATIONS 
16 
7.1. 
SAMPLE SIZE 
16 
7.2. 
STATISTICAL ANALYSIS 
16 
7.2.1. 
DATA ANALYSIS RESPONSIBILITY 
16 
7.2.2. 
DATA RETENTION 
16 
7.3. 
STUDY PARTICIPANT CONFIDENTIALITY 
16 
7.4. 
STUDY REGISTRATION 
17 
THIS STUDY WILL BE REGISTERED IN THE CLINICAL TRIALS REGISTRY: HTTP://CLINICALTRIALS.GOV/ BEFORE ITS 
BEGINNING. 
17 
8. 
SUBJECT RISKS AND BENEFITS 
17 
8.1. 
FORESEEBLE RISKS AND THEIR MINIMIZATION 
17 
8.2. 
POTENTIAL BENEFITS OF PROPOSED RESEARCH 
17 
8.3. 
ADVERSE EVENTS 
18 
9. 
ARCHIVING OF DOCUMENTS AND STUDY DATA 
18 
10. 
PROTOCOL MODIFICATIONS 
19 
11. 
PROVISIONAL STUDY CALENDAR 
19 
12. 
COMMUNICATION AND PUBLICATION RULES 
19 

       
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13. 
PARTNERSHIP 
19 
14. 
REFERENCES 
20 
15. 
APPENDIXES 
23 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

       
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1. STUDY SUMMARY 
 
TITLE 
Blood Biomarkers to improve management of mild traumatic BRAIN Injury 
implementation study 
RUNNING TITTLE 
BRAINI2 Implementation study 
GENERAL 
OBJECTIVE 
To assess the applicability and added value of a new clinical management 
pathway for patients with mild TBI presenting to the emergency 
department (ER), including the use of an in vitro diagnostic assay 
measuring the biomarkers GFAP and UCH-L1 in the serum, within the first 
12 hours post-injury, to rule out the need for CT scan in mild TBI patients. 
PRINCIPAL 
OBJECTIVE 
1) To evaluate the diagnostic performance of the VIDAS TBI 
(GFAP&UCH-L1) test in determining the need for CT-scan in 
patients with mild TBI admitted to the ER of Hospital 12 de 
Octubre. 
2)  To determine the safety of a management protocol including the 
use of the VIDAS GFAP&UCH-L1 test for patients with mTBI, in 
terms of complications or unforeseen neurological deterioration 
following the injury. 
3) To estimate the reduction of CTs achieved using the biomarker 
test, by comparison with the management of TBI during the six 
months preceding the study (reference pathway). 
PRINCIPAL 
OUTCOME 
Abnormal CT scan at admission in the ER 
Deterioration: need for hospital admission or surgery due to TBI in the first 
week after TBI 
Number of CTs prescribed in the management of mild TBI patients in the 
ER 
PRINCIPAL 
OUTCOME 
MEASURES 
 
1) Diagnostic performance of the biomarker test 
2) Proportion (%) of neurologic deterioration within 1 week post-TBI 
3)Proportion (%) of CT scan prescribed in the ER over the period of the 
study for patients with mTBI 
SECONDARY 
OBJECTIVES 
2.1) To determine the different times involved in the management of mild 
TBI patients and the effect of using the combined VIDAS test.  
2.2) To establish differences in direct costs in the management of mild TBI 
in Hospital 12 de Octubre. 
2.3.) To assess the compliance of physicians to the proposed algorithm. 
SECONDARY 
OUTCOMES 
2.1) Time from admission to discharge. Time from admission to sample 
obtention. Time from venipuncture to availability of biomarker results.  
2.2) Directs costs associated with mTBI management in the ER. 
2.3.) Compliance with proposed algorithm.  
SECONDARY 
OUTCOME 
MEASURES 
2.1) 
Time 
differences 
with 
respect 
to 
reference 
group 
2.2) Cost difference comparing before and after the implantation of the 
biomarker test.  
2.3) Proportion (%) of cases in which management follow the proposed 
algorithm 

       
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METHODOLOGY 
The study will compare the different outcome measures between a 
historic group obtained 6 months before the initiation of the new 
management protocol and the group of patients admitted in the ER with 
a diagnosis of a mTBI after the initiation of the new bundle of care.  
The combined GFAP&UCH-L1 test has been included in the new bundle of 
care of mTBI for the management in the ER of all patients with mTBI. In 
summary the test will be performed to all patients with mTBI admitted to 
the ER of Hospital 12 de Octubre and included in the new management 
pathway of patients with mTBI incorporated in our hospital. All patients 
suffering a mTBI(GCS 15-13) and admitted within 12 hours of the TBI will 
be included in this pathway. If the patient is included in this pathway, the 
prescription of cranial CT will be performed following the results of the 
VIDAS TBI test if the patient has had a significant TBI and a GCS of 14 or 
15. Those patients with GCS of 13 or a focal neurological deficit will receive 
both biomarkers and CT for their management during the study period. 
The VIDAS TBI test interpretation as defined by the manufacturer, 
bioMérieux, takes into account the responses of the two biomarkers: the 
VIDAS TBI test is negative if the two markers GFAP and UCH-L1 are 
negative (below the previously defined threshold concentration for each 
of the biomarkers). The test is positive if at least one of the two GFAP or 
UCH-L1 biomarkers is positive (beyond the threshold concentration). This 
test is already CE marked and has already been tested on a large number 
of European patients and has demonstrated good safety and reliability 
profiles.  
STUDY TYPE 
Protocol evaluation Implementation Study 
STUDY DESIGN 
Implementation study with prospective data collection with a control 
reference historic group 
STUDY 
POPULATION  
Mild TBI patients with significant brain trauma admitted in the ER of 
Hospital 12 de Octubre 
INCLUSION 
CRITERIA 
-All adult patients suffering mild TBI:( Defined by at least criterion a) and 
d) and one or more of the other criteria) 
 
a) The presence of a plausible traumatic mechanism observed/or 
related by the patient´s recount of the injury event. 
 
b) Presence of one or more clinical signs attributable to brain 
injury: Loss of consciousness immediately following injury, alteration of 
mental status immediately following the injury, posttraumatic amnesia or 
any neurological abnormality. 
 
c) At least two acute symptoms related to the injury: feeling 
confused or disoriented, headache, nausea, vomiting, dizziness, vision 
problems, memory problems, emotional lability or irritability. 
 
d) a GCS between 15 and 13, at least 30 minutes after injury. 
-Blood sample obtained ≤12 h after injury and ideally before any imaging 
prescription. 
EXCLUSION 
CRITERIA 
· GCS 3-12 on admission 
· Age Below 18 years 
· Time of injury unknown 
· Time to injury exceeding 12 hours 

       
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· Primary admission for non-traumatic neurological disorder (e.g., stroke, 
spontaneous, intracranial hematoma) 
· Penetrating head trauma 
· Patient with mechanical ventilation from the trauma scene or prehospital 
management 
· Venipuncture not feasible 
NUMBER OF 
SUBJECTS 
The implementation study will last for 6 months. The number of patients 
that are normally treated for this pathology is around 3000 patients each 
year. During the 6 months of the study around 1000 patients will at least 
be triaged for mild TBI  
STUDY CENTRES 
Hospital 12 de Octubre  
PROVISIONAL 
CALENDAR OF 
THE STUDY 
- Start of inclusions: Jan 2025 
- Inclusion period: 6 months 
- End of inclusions: July 2025 
- Length of participation of each subject: 2 weeks 
- Total length of the study: 6 months 
STATISTICAL 
ANALYSIS 
Outcome assessment 
CT scan status will be attributed to each study participant based on the 
presence of intracranial lesions. Local CT reading will be used.  
Outcome assessors will be blind to the participant biomarker status. 
Quality control outcome assessment will be performed over the study 
period via sequential intra/inter observer agreement assessment. 
EXPECTED 
IMPACT 
This study will demonstrate the feasibility of using a bundle of care based 
on the determination of blood-based brain biomarkers in the 
management of patients with mTBI, in a real-life setting. It will also 
determine the time needed for obtaining results of these blood derived 
biomarkers and if there is reduction in associated cost and CT prescription 
related to its use.  
 
 
 
 
 
 
 
 
 

       
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2. RATIONALE FOR THE STUDY 
 
2.1. Background and current management 
Traumatic brain injury (TBI) is a major large public health and societal problem with an annual 
incidence of 262 per 100.000 patients in Europe. TBI is defined as an alteration in brain 
function, or other evidence of brain pathology, caused by an external force. Clinical severity of 
TBI lies on a continuum graded by the Glasgow Coma Scale score from which TBI has been 
classified in the broad categories of "severe (GCS 3-8)", "moderate (9-12)", and "mild (13-15)". 
Research has focused for a long time in the more severe forms of TBI, due to its more evident 
catastrophic consequences to life. However, mild TBI is the more frequent form of TBI (70-80% 
of all TBI), and therefore pose the greatest health care burden caused by TBI [1,2]. The 
population affected by TBI depends on the degree of development of the country, and as the 
population ages, the number of patients affected by TBI increases, specifically in this form of 
mTBI. The most frequent cause of mTBI nowadays is falls and this incises in the aged group of 
European population. 
The initial management of mild TBI in the ED relies on performing a non-contrast brain CT if 
the patient meets specific conditions. Efforts have been made to optimize the indications for 
Brain CT scan after mTBI such as different clinical decision rules (CDRs) such as the Canadian 
Head CT rule[3] or the New Orleans criteria[4]. However the prevalence of CT detected 
abnormalities is less than 10% in patients with mTBI and a minority of these patients with 
intracranial lesions will require a neurosurgical procedure (1%).  
Several aspects are in controversy in the management of patients with mTBI. In the ER[5-8], 
the need for performing or not a CT, the value of the CDRs and protocols used in the ER to 
select those patients in need of having a CT performed and the value of serum biomarkers for 
selecting these patients in need of further examination has been thoroughly studied[9-18]. The 
variability in the management of mTBI between different hospitals within a country and in 
Europe (16)(and publication in press from our group) implies that CDRs are not correctly 
followed by physicians attending these patients due to the complexity of these rules, the 
difficulty in actually applying them in certain conditions such as intoxicated patients, hearing 
loss or speech difficulties, and the insecurity many physicians and patients have to being 
discharged without a CT. As a consequence, up to 40% of CT scans obtained in the ER would 
actually not follow these CDRs. Therefore, the number of CTs performed for this condition is 
very high, with important consequences for health expenditure and radiation exposure to 
patients. This is also a specific and important problem for elderly patients. Intracranial changes 
that occur with aging as well as the increasing prevalence of comorbidities and antithrombotic 
medication use put the elderly at an increased risk of intracranial bleeding after low velocity 
falls. Most CDRs use age over 60 or 65 as one of the factors associated with use of CT scan after 
mTBI. Elderly patients are therefore at an increased risk of CT overuse as they suffer many 
times from recurrent falls and sometimes receive one CT for each fall. 

       
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Patients with mTBI lesions are often hospitalised in the standard ward where 
neurological monitoring consists of repeated CT scanning and clinical exams. 
Patients without lesions on the initial head CT-scan are also hospitalised when their GCS score 
after CT scan is less than 15.  
Additionally, elderly patients on anticoagulants or antithrombotic drugs are more frequently 
hospitalised due to physicians’ concerns about potential deterioration. This determines a 
bigger number of unneeded hospitalisations for these patients.  
Therefore, although CT scan plays a pivotal role in the management of mTBI, there is an unmet 
clinical need for an objective tool to optimize and guide indications for CT scan, reduce clinical 
practice variability, reduce patient radiation exposure and improve patient outcome 
prediction.  
2.2. Blood Biomarkers in mTBI 
 
Serum biomarkers have appeared as a possible solution for determining the need for CT in 
patients with mTBI. S-100B has been incorporated in one of the CDR (The Scandinavian mild 
head injury management guidelines)[17,18]. However, the use of this biomarker is restricted 
to Scandinavian countries and has not gained acceptance in any other country. There are 
specific concerns regarding its negative predictive value, the variation of its concentration 
regarding skin color or the increase in its concentration when there is systemic trauma[21,22]. 
GFAP and UCHL1 are two brain specific biomarkers that have recently been demonstrated to 
have in combination a very high negative predictive value for demonstrating lesions in CT and 
there is some data regarding their possible role in determining prognosis and even their ability 
to determine which patients could have lesions detectable in MRI[23].  
Recently a new algorithm including blood biomarkers (GFAP and UCH-L1) has been proposed 
in the management of mTBI patients in Spain supported by different organizations and medical 
societies including the Spanish Neurosurgical Society. This algorithm has not yet been studied 
for its net benefit in reducing costs or the number of CTs prescribed. Additionally, there is no 
data on the time needed to provide accurate results available to the clinician. Nevertheless the 
recommended algorithm has been adopted and proposed by different medical societies, 
including the Spanish Society for emergency Medicine and the Spanish Society of Neurological 
Surgeons (SENEC). This algorithm will be adopted by the Department of Neurosurgery of this 
Hospital in order to implement this new solution.  
2.3. VIDAS TBI 
The VIDAS TBI assay is an automated, quantitative, enzyme-linked immunofluorescent assay 
(ELFA) for the detection of Ubiquitin C-terminal Hydrolase-L1 (UCH-L1) and Glial Fibrillary 
Acidic Protein (GFAP) in blood serum. The assay is to be used in conjunction with other clinical 
information, as an aid in the evaluation of adult patients with mTBI (with Glasgow Coma Scale 
score (15-13) within 12 hours of injury to assist in determining the need for a CT scan of the 
head. This assay has been assessed in the BRAINI study[24] and is now CE marked and FDA 
approved. There is no data regarding the practical use or real-world data including the use of 
the VIDAS GFAP&UCH-L1 assay. 

       
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3. STUDY OBJECTIVES AND OUTCOME MEASURES 
 
3.1. GENERAL OBJECTIVE 
 
The general objective of BRAINI-2-Implementation Study is to assess the performance of the 
biomarkers GFAP and UCH-L1 in real life and to assess their safety of use when incorporated 
into the clinical management of the patient and to establish their acceptance and integration 
into an already accepted management pathway. 
 
3.2. PRIMARY OBJECTIVE AND OUTCOME MEASURE 
 
The primary objective of the study is to evaluate the performance of the two biomarkers GFAP 
and UCH-L1 assay to rule out the need for CT scan after mTBI.  
 
The primary outcome will be the result of brain CT. Performance of the test will be analysed, 
as described in the assay instruction for use, to rule out the need for a CT scan after mTBI.  
CT results will be obtained following the usual management pathway, using local radiologist 
report to determine the presence of pathological findings. Patients in whom no CT will be 
performed (i.e.: some GCS 15 without RF and GCS 14 with negative biomarkers test), will be 
ascribed as CT negative for the analysis if there is no deterioration or further evaluation that 
determines the need for a CT for other reasons. 
Both GFAP and UCH-L1 biomarkers will be tested by two separate immunological assays using 
the usual clinical management and pathway in the management of mTBI. The positivity 
thresholds for each of the biomarkers and the two biomarkers’ combination were validated by 
the company Banyan Biomarkers in an independent study, ALERT-TBI [13] and confirmed by 
bioMérieux using the VIDAS TBI with the same ALERT-TBI cohort and with the BRAINI study. 
The test will be performed if the patient is included in the new management pathway of 
patients with mTBI incorporated in our hospital. If the patient is included in this pathway, the 
prescription of cranial CT will be performed following the results of the VIDAS TBI test 
obtained. Patients with GCS of 13 will receive both biomarkers and CT scan for their 
management. Patients not following the clinical pathway (GCS<13 or non TBI patients) will be 
excluded from the study and managed according to routine clinical practice. 
The VIDAS TBI test interpretation as defined by the manufacturer, bioMerieux, takes into 
account the responses of the two biomarkers: the VIDAS TBI test is negative if the two markers 
GFAP and UCH-L1 are negative (below the previously defined threshold concentration for each 
of the biomarkers). The test is positive if at least one of the two GFAP or UCH-L1 biomarkers is 

       
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positive (beyond the threshold concentration). This test has been already tested in a 
large number of European patients and has presented good safety and reliability 
profiles.  
To determine the safety of the new protocol all information regarding the neurological status 
of the patients in relation to mTBI will be analyzed up to two weeks after the mTBI, specifically 
neurological deterioration, need for further observation of the patient or admission or need 
for treatment(medical or surgical) related to mTBI.  
In order to determine the reduction of CT scans obtained with this new protocol, absolute 
numbers and proportions of patients finally scanned using this new protocol will be compared 
to the reference management of a similar number of patients during a similar historical 
period(i.e. data from the previous six month for patients attended for mTBI at Hospital 12 de 
Octubre). 
3.3. SECONDARY OBJECTIVES AND OUTCOME MEASURES 
 
Different secondary objectives are planned in this study with corresponding outcome 
measures: 
3.3.1. Time lapse needed in the management of mTBI in the ED: 
 a)From TBI to VIDAS TBI result.  
b)From admission to VIDAS TBI result available for physician.  
c)From TBI to CT and from admission to CT.  
d)General management of TBI in the ER.  
Outcome measures will be time to achieve each these steps in management, 
obtained directly from the Hospital´s information and data systems.  
 
3.3.2. Direct costs consumption will be obtained from each ER episode of included 
patients and compared to age-matched historical controls (patients 
managed in Hospital 12 de Octubre for mTBI in the previous six months 
before implementation of the new protocol).     
 
3.3.3. Assessment of the proportion of cases being managed following the proposed 
algorithm 
4. STUDY DESIGN 
 
4.1. STUDY OVERVIEW AND STUDY POPULATION 
 
This is a single center study with prospective data collection with a control reference group.  
Patients to be included in the new clinical pathway: 
-Adult Patients (≥18 years of age) suffering mild TBI:( Defined by at least criterion a) and e) 
and one or more of the other criteria) 

       
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a) The presence of a plausible traumatic mechanism as described by the 
patient´s recount of the injury event. 
 
b) Presence of one or more clinical signs attributable to brain injury: Loss of 
consciousness immediately following injury, alteration of mental status immediately following 
the injury, posttraumatic amnesia or any neurological abnormality. 
 
c) At least two acute symptoms related to the injury: feeling confused or disoriented, 
headache, nausea, vomiting, dizziness, vision problems, memory problems, emotional lability 
or irritability.  
 
e) GCS between 15 and 13, assessed at least 30 minutes after injury. 
-Blood sample obtained ≤12 h after injury and before any imaging prescription. 
 
Patients will not be included in the new pathway if: 
· GCS 3-12 on admission 
· Time of injury unknown 
· Time to injury exceeding 12 hours 
· Primary admission for non-traumatic neurological disorder (e.g., stroke, spontaneous, 
intracranial hematoma) 
· Penetrating head trauma 
· Patient with mechanical ventilation from the trauma scene or prehospital management. 
· Venipuncture not feasible 
Participation in the study will not affect patient management. 
5. BRAINI2-IMPLEMENTATION PROCEDURE 
 
5.1. STUDY ENROLLMENT METHOD AND FEASIBILITY 
Use of the biomarkers GFAP and UCH-L1 being part of the 2023 guidelines for management of 
mTBI in Spain, and being now included in the new clinical management pathway in the hospital 
12 de Octubre, all patients with mTBI admitted to the ER of the study site and answering to 
inclusion and exclusion criteria of the study will be considered for participation in this study. 
All patients assessed for mTBI will be considered for inclusion in the mTBI management bundle. 
This bundle of care, already accepted in the Department will include obtention of blood 
biomarkers by venepuncture. Patient management will not be altered by the study. De-
identified patient data will be obtained from the clinical records and will be studied. All data 
obtained is recorded for the normal management of mTBI patients and therefore no extra 
information will be obtained. No further contact with the patient will be made outside of their 
normal interactions at the Hospital and with their general practitioner. Records from the 
electronic clinical records will be the only source of data in this study both in the acute setting 
and in the follow up of the patients.  
 

       
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5.2. STUDY TIMELINE AND PLANNED MANAGEMENT ALGORITHM 
 
All patients with TBI admitted to the ER and with a GCS between 13 and 15 will receive a blood 
test for biomarker determination upon admission. All patients with GCS of 13 or with a focal 
neurological deficit on admission will receive a CT. CTs could be performed to GCS14 and 15, 
independently of the result of the combined test, but the results of the test will be taken into 
consideration to guide for prescribing a CT. The attending physician will be responsible for the 
management of the patient and will have to determine the reason to prescribe CT despite 
normality of the biomarker test. The management algorithm that is recommended is as 
follows: 
 
 
 

       
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Risk factors (RF) include: 
-Loss of consciousness. 
-Postraumatic amnesia (anterograde or retrograde). 
-Advanced age (over 65) 
-Antithrombotic treatment including platelet inhibitors. 
-Difficulty in assessing level of consciousness: Cognitive impairment, intoxication. 
-Persistent symptomatology: Repeated vomiting, persistent headache. 
-High energy or High-risk mechanism: Falls over one’s height, car accident, pedestrian involved 
in traffic accident, or accidents in which other there are other seriously injured patients.  
Data will be collected directly from a specified structured form in the electronic health record 
of the patient. All data will be pseudonymised. Information regarding follow up will be 
recorded from the electronic health record regarding new contacts with the hospital or need 
of further assessment. 
 
5.3. PARAMETER ASSESSMENTS 
 
5.3.1. 
Clinical parameters 
1) Vital signs will be measured in the emergency department according to standard practice 
(GSC score, arterial blood pressure, heart rate, respiratory rate, body temperature, pulse 
oximetry). The presence of vomiting, nausea or headache will be recorded, as well as the 
presence of loss of consciousness. All recorded variables will be obtained following the 
standard of care of the workup of the mTBI patient stablished in the Hospital and no extra 
information will be obtained.  
Secondary deterioration within the first week after TBI will be obtained by reviewing electronic 
medical history of the patient´s and new contacts during this week with the ER, and is defined 
as follows: 
· a decrease in GCS score of more than 2 points from the initial GCS score in the absence 
of sedatives 
· a deterioration in neurologic status sufficient to warrant intervention, i.e. mechanical 
ventilation, sedation, osmotherapy, neurosurgical procedure or admission to the intensive 
care unit. 
· Admission to a hospital ward exclusively related to deterioration of neurological condition 
due to TBI. 

       
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5.3.2. 
Biological assessments (BA) 
 
Blood samples will be drawn only for the management of patients with mTBI, as established 
by the mTBI care bundle and within 12 hours after TBI. The volume of blood collected will be 
that necessary to obtain results for both GFAP and UCH-L1 biomarkers. Permission for 
obtention of this blood sample will follow the normal standard of care of any other blood 
sample obtained in the ER. For normal health care management of patients admitted due to 
mild TBI in which a CT scan is going to be performed, laboratory analysis regarding hemogram 
and formula, coagulation status (Prothrombin time (PT), INR and aPTT) and conventional 
biochemistry analysis (Na, K, glycemia, creatinine, AST and ALT) are normally obtained by local 
laboratories as a standard of care. These data of the conventional laboratory analysis 
performed to these patients as standard of care will be obtained and stored in the eCRF. 
 
5.3.3. 
DATA COLLECTION AND DATA MONITORING 
 
Data obtained as standard of care for the management of mTBI will be collected in the 
electronic clinical records. The Electronic Health Record is an essential tool for clinical decision-
making and data collection, as it enables accurate and systematic documentation of patient 
information. However, its full potential is exploitable and useful when the data is structured. 
For this reason, and since the TBI information will be collected in the HER(Electronic Health 
Record), the hospital's IT data area improved the structuring and standardization of the 
information in the EHR. To this end, the mTBI diagnostic code was unified and codified 
(SNOMED CT) and a form was created with the questions that are asked when attending a 
patient with TBI. The completeness of the defined diagnosis together with the designed form 
will allow the identification of the cohort of patients with mTBI. In addition to the data included 
in the form, the study will collect demographic and baseline information at admission, the 
reason to prescribe brain CT scan and immediate CT findings by the local radiologist, biological 
data if indicated by the in-charge physician.  
At 10 days postTBI, clinical research associates will review all information regarding the 
neurological status of the patients and the need for hospitalisation or other contacts to the ER 
in relation to mTBI. This review will be done thanks to the previous automatic extraction of the 
mTBI data collected in the EHR.   
Regular quality checks on the information consigned in the EHR by attending physicians will be 
performed as a program for quality improvement of mTBI bundle. This program has been 
already run by the Department of Neurosurgery in order to enhance the recording of 
structured data in clinical records in our hospital. For this purpose, a dashboard in Power 
Business Inteligence (PowerBI) has been designed. In addition to functioning as an instrument 
for monitoring data recording, this PowerBi dashboard will also show the indicators outlined 
below for the purpose of protocol evaluation. These are time of care in the emergency 
department for patients with mTBI, percentage of CT requested, percentage of CT requested 

       
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in patients with negative biomarkers, percentage of CT requested in patients with 
positive biomarker, percentage of pathologic CT in patients with positive biomarker, 
percentage of pathologic CT in patients with negative biomarker, percentage of patients 
requiring admission and percentage of second ED visit after discharge.  
Finally, the de-identified data from the mTBI cohort will be obtained and transferred into a 
web based electronic CRF(eCRF) built on RedCap to be able to be analysed. The database in 
RedCap will contain pseudo-anonymised clinical information about the patients with mTBI 
from six months prior to the implementation protocol and information from six months of the 
implementation protocol. 
5.3.4. 
CT SCAN ANALYSIS 
 
Brain CT scans are performed as part of the patient standard of care. CT scan findings are 
classified as CT negative or CT positive by local reviewers.  
The criteria for CT positivity are crucial because the primary objective is related to the CT 
results (positive/negative). Criteria for CT-positive findings are as follows: a CT scan classified 
as type II or greater according to the Traumatic Coma Databank classification (range I–V), or a 
CT scan with the presence of the following lesions: (1) epidural haematoma, (2) subdural 
haematoma, (3) subarachnoid haemorrhage, (4) intraventricular haemorrhage, (5) contusion, 
(6) petechial haemorrhage or (7) any finding related to diffuse axonal injury and depressed 
skull fracture. Linear skull fractures will be recorded but not used for the definition of CT 
positive lesions. Subdural hypodense hygromas, calcifications, ischemia will not determine a 
positive qualification. Nevertheless, all findings will be recorded by. Radiologist will be trained 
to assess CTs regarding the following classification. 
Items that WILL classify CT as positive 
Items that will NOT classify CT as positive 
Epidural hematoma 
Subdural hygroma 
Acute or subacute subdural hematoma 
Chronic subdural hematoma (no high intensity 
lesion inside the hematoma) 
Indeterminate extra-axial hemorrhage 
All parenchymal or extraparenchymal 
calcifications 
Subarachnoid hemorrhage 
Brain tumors 
Intraventricular hemorrhage 
Linear non-depressed fracture 
Depressed cranial fracture 
Cranial base fracture 
Brain contusion (including high intensity/mixed 
lesions and hypodense lesions) 
Pneumoencephalus 
Intraparenchymal traumatic hematoma 
Hypodense chronic Ischemic lesions 
Brain swelling 
Facial fractures 
Petechial hemorrhage 
Scalp injury 
Gliding contusions 
 
Signs of traumatic axonal injury (hyperdense 
lesions in brainstem or corpus callosum) 
 
Brain Swelling or oedema 
 
Compressed cisterns 
 
 
 
 

       
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6. STUDY STOPPING RULES 
 
6.1. STUDY STOPPING CRITERIA FOR A PARTICIPATING SUBJECT 
Participants will be excluded from the study and replaced in case of a violation of an inclusion 
criterion, e.g. in the mTBI group: no mild TBI, no CT scan when the patient should have received 
one according to the study design, no blood sampling or after 12 hours post-injury. 
7. STATISTICAL CONSIDERATIONS 
 
7.1. SAMPLE SIZE 
 
The primary endpoint of the study is to replicate the diagnostic performance of the VIDAS TBI 
assay to predict whether the tested patient would be positive or negative from brain injury 
visible on head CT scan and to determine that implementation of the VIDAS TBI, in the standard 
of care of patients with mTBI, is not associated with serious side effects during the six-month 
period of the study. We expect to test during a six-month period around 1000 patients (from 
the 3500 patients with suspected TBI that are admitted to our hospital yearly approximately 
(data from discharge diagnosis of patients with TBI related diagnostic codes)). With this sample 
size and with an expected prevalence of 10% of CT positivity we expect to have at least 100 
patients with positive CTs. With this sample size we expect to replicate the NPV of the BRAINI 
study with an expected lower bound of the 2-sided 95% CI greater than or equal to 97.0%.  
 
7.2. STATISTICAL ANALYSIS 
 
7.2.1. 
DATA ANALYSIS RESPONSIBILITY 
 
SERMAS will be responsible for the data analysis for the primary study objective (performance 
evaluation of the VIDAS TBI assay) in collaboration with BioMérieux. Data analysis for the 
secondary objectives will be performed by SERMAS. 
7.2.2. 
DATA RETENTION 
 
The site must retain its clinical trial records relating to the trial for at least 3 years after the 
clinical trial is completed or terminated. 
 
7.3. STUDY PARTICIPANT CONFIDENTIALITY 
 

       
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Gathering and processing of personal data will be done in keeping with article 9 of 
European Regulation on data protection 2016/679 (General Data Protection 
Regulation) and the counsel on data Protection of 27th April 2016. It will follow the Spanish 
Organic Law on Personal data Protection 3/2018.  
To protect the participant‘s confidentiality, data will be pseudonymised.  
 
ETHICAL AND REGULATORY CONSIDERATIONS 
The study will be conducted in accordance with the Declaration of Helsinki (amended at 
Fortaleza in 2013; for full version see http://www.wma.net), Good Clinical Practice Guidelines 
(GCP, ICHE6) and all applicable local regulations. 
The study will only begin after receiving the approval of the local ethics committee and the 
waiver of specific informed consent, as the practice will be following standard management of 
TBI.  
The Principal Investigator is responsible for ensuring compliance with these regulations, and 
adherence to protocols that have been approved by the ethics committee. 
 
7.4. STUDY REGISTRATION 
This study will be registered in the clinical trials registry: http://clinicaltrials.gov/ before its 
beginning.  
  
8. SUBJECT RISKS AND BENEFITS 
 
8.1. FORESEEBLE RISKS AND THEIR MINIMIZATION 
No therapeutic interventions will take place in the context of the implementation studies. 
Diagnostic interventions include blood sampling, outcome assessments and CT imaging. All of 
them will be based on activities performed for the actual management of mTBI in the Hospital 
and accepted and promoted by different medical societies in our country. CT imaging is 
performed as a standard of care. Blood sampling for biomarker assessment and/or other 
determinations will be performed depending on clinical indication by the attending physician 
and related to the accepted protocol for managing mTBI.  
 
8.2. POTENTIAL BENEFITS OF PROPOSED RESEARCH 
There is no direct benefit for the patients. The results will be directly relevant to society in 
general and to future patients who suffer mTBI and will help policy makers to promote the 
mTBI bundle of care devised in our hospital.  

       
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The results of this study could have a major impact on the management of patients 
with TBI: 1) By reducing the number of unnecessary CT scans; 2)by improving 
management of patients being at risk as patients testing positive could be managed in a more 
urgent way(those patients with more probability of having a lesion in CT); and 3)by a more 
objective management of patients.  
8.3. ADVERSE EVENTS 
No structured adverse event reporting will be implemented. However, we will capture any 
serious complication which may occur during the clinical course in the CRF and analysing the 
clinical records.  
 
9. ARCHIVING OF DOCUMENTS AND STUDY DATA 
 
In accordance with Good Clinical Practice the following documents related to this research are 
to be archived: 
By the physician investigators: 
- for a period of 15 years following the end of the study 
 The protocol and any amendments to the protocol 
The case report books 
 The source files of all included participants 
 All other documents and correspondence relating to the study 
 
All these documents are the responsibility of the investigator during the archiving period. 
By the sponsor: 
- For a period of 15 years following the end of the study 
  
The protocol and any amendments to the protocol 
All other documents and correspondence relating to the study 
All these documents are the responsibility of the sponsor during the archiving period. 
No displacement or destruction of documents or data can be carried out without the 
agreement of the sponsor. At the end of the regulatory archiving period, the sponsor will be 
consulted concerning destruction. All data, documents and reports may be subject to audit or 
inspection. 

       
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10. 
PROTOCOL MODIFICATIONS 
 
A substantial change is a modification likely to have a significant impact on the protection of 
the study participants, on the validity of the study or its results, on the interpretation of 
scientific documents that support the study design or conduct. A substantial change is subject 
to a written amendment submitted to the sponsor. 
All amendments are validated by the sponsor, and by all study stakeholders. Prior to its 
implementation, the sponsor must obtain a favourable opinion from the ethics committee 
(CPP). All investigators will be informed of any amendment to the study protocol. 
11. 
PROVISIONAL STUDY CALENDAR 
 
-Staff training and technology deployment: January_March 2025  
-Start of inclusions: April 2025  
- Length of inclusion period: 6 months 
- End of inclusions: September 2025 
- Length of participation of each subject: 10 days 
- Total length of the study: 12 months 
12. 
COMMUNICATION AND PUBLICATION RULES 
 
Data analysis will result in a written report that will be submitted by the sponsor, who shall 
submit it to the ethics committee. Any written or oral communication of research results must 
receive prior approval of the coordinating investigator and of any committee established for 
the research. The publication of the main results must indicate in the acknowledgements the 
name of the sponsor and investigators, methodologists, biostatisticians and data managers 
who substantially participated in the research, and the name of the funding source. The name 
of any person contributing to writing or editing the manuscript, if not already in the author list, 
should also be given in the acknowledgements. Publication will follow international standards 
of writing and publishing (The Uniform Requirements for Manuscripts of the ICMJE, April 2010) 
and respect the criteria for authorship. 
13. 
PARTNERSHIP 
The BRAINI2 study has received financial support from the European Institute of Innovation 
and Technology (EIT Health) for the business plan 2022-2024. SERMAS (Hospital Universitario 
12 de Octubre and FIBH12O Madrid), Grenoble University Hospital (CHUGA) and the University 
Grenoble Alpes, Institút Catalá de la Salut (Hospital Váll D´Hebron), Hospital of the Technical 

       
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University of Munich (TUM Klinikum), CHU Nantes, CHU-Clermont-Ferrand, Luzerner 
kantosspital, association Daño Cerebral Invisible and BioMérieux are partners to 
conduct the project. 
14. 
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15. 
APPENDIXES 
 
Appendix 1: mTBI bundle of care. 
These documents are available in separate files.