Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI)
Conditions: Traumatic Brain Injury
Sponsor: University Hospital, Antwerp

 
 
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Study Protocol  
Collaborative European NeuroTrauma Effectiveness research in TBI: a prospective 
longitudinal observational study 
 
 
 
 
NCT02210221 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
Version 4.1 
2 
03 July 2014 
 
 
 
 
 
Study Protocol  
Collaborative European NeuroTrauma Effectiveness research in TBI: 
a prospective longitudinal observational study 
 
 
 
Short study title:  
 
CENTER-TBI study 
 
Protocol: 
 
 
version 4.1 
 
Version date:   
 
03 July 2014 
 
Coordinators:   
 
Andrew IR Maas, Antwerp University Hospital 
 
 
 
 
David K Menon, University of Cambridge 
 
Funded: 
 
 
by the European Union FP 7th Framework program (grant 602150) 
 
 
 
 
 
Contract Research Organization: ICON plc, (Dublin, Ireland) 
 
Data entry tool developed by:  QuesGen (Burlington, CA, USA) 
 
Neuroimaging repository:  
Icometrix, Antwerp, Belgium 
 
Database and data analysis platform: Coordinated by the International Neuroinformatics 
Coordinating Facility (INCF) with additional support from One Mind for Research  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Study synopsis 
 
Full study title 
Collaborative European NeuroTrauma Effectiveness research in TBI: a 
prospective longitudinal observational study 
Short study title 
CENTER-TBI study 
Study Design 
Longitudinal prospective observational cohort  
Study centers 
Approximately 80 centers from 21 countries in Europe and Israel  
Study population 
Patients with traumatic brain injury 
Funding source and 
international context 
Funded by the European Union FP7 framework program (grant 602150) 
with additional national and local institutional support.  
CENTER-TBI is an InTBIR project (International Initiative for Traumatic Brain 
Injury Research: http://intbir.nih.gov/)  
Funding of additional elements has been provided by the Hannelore Kohl 
Foundation (Germany) and by the non-profit organization One Mind For 
Research (directly to INCF). 
Study objectives 
The global aims of the study are to: 
- 
Improve characterization and classification of TBI in Europe, with inclusion of emerging 
technologies. 
- 
To identify the most effective clinical care and to provide high quality evidence in support of 
treatment recommendations and guidelines. 
 
Secondary objectives: 
- 
To collect high quality clinical and epidemiological data with repositories for neuro-imaging, 
DNA, and serum from patients with TBI. 
- 
To refine and improve outcome assessment and develop health utility indices for TBI. 
- 
To develop multidimensional approaches to characterisation and prediction of TBI. 
- 
To define patient profiles which characterise homogenous subgroups of patients and predict 
efficacy of specific interventions (“Precision Medicine”). 
- 
To develop performance indicators for quality assurance and quality improvement in TBI care. 
- 
To validate the common data elements (CDEs) for broader use in international settings. 
- 
To develop an open source database compatible with FITBIR. 
- 
To intensify networking activities and international collaborations in TBI.  
- 
To disseminate study results and management recommendations for TBI to health care 
professionals, policy makers and consumers, aiming to improve health care for TBI at individual 
and population levels. 
- 
To develop a “knowledge commons” for TBI, integrating CENTER-TBI outputs with systematic 
reviews  
Study design  

 
 
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Methodology 
This study will be a multicentre longitudinal prospective observational, 
cohort study conducted in 21 countries across Europe and Israel.  
Data collection for CENTER-TBI will take place at 2 levels: CENTER-TBI 
registry (all patients) and CENTER-TBI Core data collection (patients 
meeting inclusion and exclusion criteria; detailed data collection). 
Number of subjects 
CENTER-TBI core data study: the planned total number of subjects will be 
5400 equally distributed across three strata: 
- 
ER stratum: patients seen and discharged from the ER 
- 
Admission stratum: patients admitted to hospital but not to the 
ICU 
- 
ICU stratum: patients admitted directly to the ICU  
 
CENTER-TBI registry: 15.000-25,000 
Inclusion criteria for 
observational study 
1. Clinical diagnosis of TBI 
2. Clinical indication for CT scan 
 
Inclusion criteria for 
core data study 
 
Exclusion criteria for 
core data study 
1. Presentation within 24 hours of injury 
2. Informed consent obtained according to local and national requirements 
 
Severe pre-existing neurological disorder that would confound outcome 
assessments 
 
Extended studies 
 
Selected sites, meeting additional logistic requirements, will participate in 
extended data collection with regard to: 
 
- MR imaging 
- Extended coagulation and biomarker studies 
- Acquisition of high resolution ICU monitoring data 
 
Study Interventions 
Therapeutic 
interventions 
None 
 
Diagnostic 
interventions 
- 
Registry: none 
- 
Core study: blood sampling on presentation, in the ICU stratum 
during the clinical course and in all strata at follow up 
- 
Follow up assessments  
 
Data collection 
Registry 
Only observational data collected, without formal consent, in the context 
of routine clinical care 
 
Core study 
Prospective collection of clinical data with informed consent. 
Blood collection: 
- 
Hematology 
- 
Biochemistry 
- 
Genotyping 
- 
Biomarker analysis 
- 
Coagulation studies 
CT scan as part of routine clinical care 
Outcome assessments 
 

 
 
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Study endpoints 
Registry: Vital status, injury severity indices, and discharge destination 
 
Core data collection: 
Cross sectional comprehensive outcome assessments across the three strata of recruitments in all 
subjects at 6 months; these assessments will include health related quality of life, psychological and 
neuropsychological testing (CANTAB). 
 
Longitudinal assessments of outcome by telephone, postal questionnaire and/or face-to-face visits 
will be performed at various time points in the three strata up to 24 months after injury (focus on 
more early outcome assessments in ER stratum and later assessments in admission in ICU strata). 
  
Analysis directions in the context of the CENTER-TBI project 
The registry and core data study will form the basis of the scientific analysis described in the 
Description of Work of the CENTER-TBI project (funded by the European Union FP 7 program grant 
602150).    
Analysis of the CENTER-TBI core data and CENTER-TBI registry will be in two directions:  
1. Improved characterization of disease 
2. Identification of best practice, addressing both variations in process and in clinical care, and 
including the use of stratified/personalized approaches.  
Results of the analyses will be integrated with results of ongoing living systematic reviews in a 
process of knowledge transfer aiming to provide practical evidence based recommendations.  
 
WP19
Communication, education, dissemination 
and implementation
WP18
Knowledge transfer and guideline 
development
CENTER-TBI
Core Study
n = 5400
CENTER-TBI registry
n = 15 000-25 000
Repositories
Characterization of TBI
WP7-12
CER approaches for 
defining
effective clinical care
WP13-17
Legacy research
Analysis
39 scientific participants
Data collection
80 centres
Translational Impact
 
 
 
 

 
 
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Sample size justification  
A total sample size of 5400 patients is planned for the Core Data Study with enrolment of 
approximately 1800 per stratum.  
 
This sample size estimate was based on: 
 
Practical logistic considerations  
 
Power calculations for the different strata, targeting comparative effectiveness analyses, 
assuming a between-centre and between-countries differences as previously observed in TBI 
research 
 
Postulated odds ratios for intervention effects of approximately 5% improvement in outcome.  
 
Overall, these calculations provided a statistical power to detect odds ratios of ~1.2 associated with 
differences in process or intervention variables across the core dataset with a power of 80%; and 
somewhat larger odds ratios in each of the 3 individual strata.   
In the registry we expect to be able to detect differences (predominantly in organizational or system 
variables) with an odds ratio of 1.2 with a power of 82%.        
   
Statistical analysis plan 
Statistical analyses for the Comparative Effectiveness Research (CER) questions will primarily apply 
random effects modeling, in which center is included at the highest level, and patients are 
considered clusters within centers. Confounding factors as measured at the individual patient 
and/or center level, will be considered. 
Statistical analyses for better characterization of TBI will be mainly exploratory. Standard statistical 
descriptive and inferential techniques, as well as machine learning techniques will be used. 
Prognostic analyses will consider a range of variables, including genetic, biomarker, neuro-imaging 
and additional outcome assessments. Previously and newly developed prediction models will be 
validated by measures for model fit, discrimination, and calibration. 
 
 
 

 
 
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Overall goals and impact of CENTER-TBI 
The CENTER-TBI project will contribute towards the overall goals of InTBIR, by identifying more 
effective and efficient treatment provision, thus improving outcome and reducing costs. The science 
in the project will provide methodological advances (including novel, multilingual translations of key 
outcome instruments), novel information on disease processes, treatment, outcome, and prognosis 
in TBI, identifying new therapeutic targets and therapies; while the CENTER-TBI repositories will 
ensure opportunities for legacy research. Thus, the project has the potential to improve current 
health care and its delivery at both population and individual levels, deliver early scientific advances 
that could improve the care of patients with TBI, and provide a rich investment for future 
biomedical and clinical research.  
Accurate
Diagnosis
Targeted
Treatment
Precision
medicine
Improved
Health
Benchmarking 
quality of care
Improved 
prognostic 
models
Knowledge Network
Injury exposome
Signs/symptoms
ICU physiome
Neuroimaging
Genome
Biomarkers
Individual patients
Information Commons
Improved disease 
characterisation
CER identifies 
most effective 
treatments
Bioinformatics
(data integration)
CENTER-TBI study: data collection 
during normal course of clinical care
Personalized
approaches
 
 
Figure 3.2: The CENTER-TBI participants represent a knowledge network that will analyze the clinical database and associated 
biorepositories.  This highly granular “information commons”, aided by novel bioinformatic approaches, will improve disease 
characterization, resulting in a new taxonomy of TBI (Precision Medicine). Clinical data will be subjected to CER analysis, both directly, 
and after refinement with precision medicine to identify more effective and targeted therapies.  The increased data inputs will improve 
prognostic accuracy, allowing better benchmarking of care (Adapted from National Research Council). 
 
 
 
 
 

 
 
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Schedule of events 
Schedule of Assessments - ER Stratum  
 
Visit Name 
 
Acute 
≤ 72 hours from injury 
2-3 weeks 
3 month 
6 month 
Consent Subject/Consultee/Brief 
xa 
 
 
 
 
Re-Consent 
 
xb 
xb 
xb 
xb 
Emergency Room eCRF 
x 
 
 
 
 
Post Discharge eCRF 
 
 
x 
X 
x 
Biomarker  
X (1800) 
 
X (600) 
X (200) 
 
Genetics  
X (1800) 
 
 
 
 
Routine Local Haemostasis 
Xf (1800) 
 
 
 
 
Extended Local Haemostasis 
Xg (600) 
 
 
 
 
Central Haemostasis 
 
 
 
 
 
Ultra Early MRI 
 
Xc (200) 
 
 
 
MRI 
 
 
X (600) 
Xe (250) 
 
Neuropsychology Follow-Up 
 
 
Xd (600) 
X (600) 
X (1150) 
Questionnaire Follow-Up 
 
 
X (1400) 
X (1300) 
X (1250) 
 
 
 
 
 
 
 
a 
Consent procedure will depend on capacity assessment 
b 
Only if required 
c 
Only in sites participating in UE MR arm 
d 
Only in patients undergoing MR studies 
e 
Target patients with abnormalities on previous MR  
(patients who have a normal MR at 2-3 weeks will not be invited for repeat imaging) 
f 
Record routine clinical bloods if obtained in the eCRF 
g 
Only in sites participating in extended haemostatis arm 
* Figures in brackets represent the number of subjects 
targeted for the procedure in that stratum (this 
accounts for funding constraints, mortality, loss to 
follow-up and feasibility) 
 

 
 
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Schedule of Assessments – Admission Stratum  
Visit Name 
 
Acute 
Day 
1-7 
Day 
10 
Day 
14 
Day 
21 
Day 
28 
2-3 
weeks 
3 
Month 
6 
month 
12 
month 
24 
month 
Consent Subject/Consultee/Brief 
xa 
 
 
 
 
 
 
 
 
 
 
Re-Consent 
 
xb 
xb 
xb 
xb 
xb 
xb 
xb 
xb 
xb 
xb 
Admission eCRF 
x 
xc 
xc 
xc 
xc 
xc 
 
 
 
 
 
Post Discharge eCRF 
 
 
 
 
 
 
x 
x 
x 
x 
x 
Biomarker 
X 
(1800) 
 
 
 
 
 
 
 
X 
(1200) 
X 
(300) 
X 
(250) 
Genetics  
X 
(1800) 
 
 
 
 
 
 
 
 
 
 
Routine Local Haemostasis 
Xi 
(1800) 
 
 
 
 
 
 
 
 
 
 
Extended Local Haemostasis 
Xj 
(600) 
 
 
 
 
 
 
 
 
 
 
Central Haemostasis 
Xj 
(600) 
 
 
 
 
 
 
 
 
 
 
Ultra Early MRI 
Xh 
(200) 
 
 
 
 
 
 
 
 
 
 
MRI 
 
 
 
 
 
 
Xe 
(600) 
 
Xf 
(600) 
Xg 
(300) 
Xg 
(150) 
Neuropsychology Follow-Up 
 
 
 
 
 
 
 
 
X 
(1200) 
Xd 
(300) 
Xd 
(250) 
Questionnaire Follow-Up 
 
 
 
 
 
 
 
X 
(1450) 
X 
(1300) 
Xk 
(1200) 
X 
(250) 
 
 
 
 
 
 
 
a 
Consent procedure will depend on capacity assessment 
b 
Only if required 
c 
Only if an in-patient 
d 
Only in patients undergoing MR studies 
e 
Attempt to target patients who had UE MR at <72 hours 
f 
Attempt to target patients who had MR imaging at 2-3 weeks 
g 
Target patient who had MR imaging at 6 months 
h 
Only in site participating in UE MR arm 
i 
Record routine clinical bloods if obtained in the eCRF 
j 
Only in site participating in extended haemostatis studies 
k 
These patients will not have MR imaging 

 
 
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Schedule of Assessments – ICU Stratum  
Visit Name 
 
Acute 
Post op 
Day 1 
Day 3 
Day 4 
Day 5 
Day 
6-7 
Day 
10 
Day 14 
Day 21 
Day 28 
2-3 wks 
3 mth 
6 mth 
12 mth 
24 mth 
Consent 
Subject/Consultee/Brief 
xa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Re-Consent 
 
 
xb 
xb 
xb 
xb 
xb 
xb 
xb 
xb 
xb 
xb 
xb 
xb 
xb 
xb 
ICU eCRF 
x 
 
xc 
xc 
xc 
xc 
xc 
xc 
xc 
xc 
xc 
 
 
 
 
 
Post Discharge eCRF 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
x 
x 
Biomarker  
X (1800) 
 
X (1000) 
X 
(250) 
X 
(250) 
X 
(250) 
 
 
 
 
 
X 
(600) 
 
X 
(1200) 
X 
(300) 
X 
(250) 
Genetics  
X  (1800) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Routine Local Haemostasis 
X  (1800) 
X (300) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Extended Local Haemostasis 
X (600) 
X (300) 
X (600) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Central Haemostasis 
X 
 (600) 
X 
(300) 
X (600) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ultra Early MRI 
Xh (200) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MRI 
 
 
 
 
 
 
 
 
 
 
 
Xe 
(600) 
 
Xf 
(600) 
Xg 
(300) 
Xg 
(150) 
HR-ICU 
xj 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EcoG 
xj 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EEG 
xj 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neuropsychology Follow-Up 
 
 
 
 
 
 
 
 
 
 
 
 
 
X (1200) 
Xd (300) 
Xd (250) 
Questionnaire Follow-Up 
 
 
 
 
 
 
 
 
 
 
 
 
X (1450) 
X (1300) 
Xk (1200) 
X (250) 
 
 
 
 
 
a 
Consent procedure will depend on capacity assessment 
b 
Only if required 
c 
Only if an in-patient 
d 
Only in patients undergoing MR studies 
e 
Attempt to target patients who had UE MR at <72 hours 
f 
Attempt to target patients who had MR imaging at 2-3 weeks 
g 
Target patient who had MR imaging at 6 months 
h 
Only in site participating in UE MR arm 
i 
Only in site participating in extended haemostatis studies 
j 
Only in centres participating in these extended studies 
k 
These patients will not have MR imaging