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

1. Introduction and rationale

The CENTER-TBI core data study and CENTER-TBI registry form part of the
CENTER-TBI project: Collaborative European NeuroTrauma Effectiveness Research
in TBI, a large scale project funded by the European Union Framework 7 program
(grant 602150). The research aims are to: 1) better characterize Traumatic
Brain Injury (TBI) as a disease and describe it in a European context and 2)
identify the most effective clinical interventions for managing TBI.

Each year approximately 2.5 million people will suffer from some form of TBI in
Europe; of these 1 million will be admitted to hospital and 75.000 will die.
TBI thus constitutes a major cause of death and disability, leading to great
personal suffering to victims and relatives and huge direct and indirect costs
to society. In the US, the annual burden of TBI has been estimated at over 60
billion USD in patients with severe TBI. The life time cots per case is
estimated at 396.000 USD with disability and lost productivity costs
outweighing medical and rehabilitation costs by a factor 4.

TBI is considered *the most complex disease in our most complex organ*. It is
characterized by great heterogeneity in terms of etiology, mechanisms,
pathology, severity, and treatment, with widely varying outcomes. Falls and
high velocity road traffic incidents cause different types of injury. TBI may
consist of diffuse damage, contusional brain damage, or intracranial hematomas.
Some structural abnormalities (particularly traumatic axonal injury) may be
poorly detected by conventional imaging. The clinical severity of TBI ranges
from minor (minimal complaints, no visible structural damage) to virtually
unsurvivable injuries. We have found large differences in outcome between
centres with up to a six fold higher risk in *poorer* vs. *better* centres
after adjustment for chance effects and case mix (Lingsma et al 2011). We now
also recognize that TBI is not just an acute event, but can trigger a chronic
process, with progressive injury over hours, days, weeks, months, and even
years (Masel & DeWitt 2010). Whilst basic research has increased our knowledge
of the mechanisms involved, improvements in clinical management have not kept
pace. Guidelines for the treatment of TBI are available (www.tbiguidelines.org;
www.nice.org.uk) but the evidence underpinning these recommendations is weak.
Moreover, current approaches to the characterization of disease severity and
outcome are uni-dimensional and have not undergone refinement for more than
three decades. Treatment generally follows a *one size fits all* approach and
is not targeted to the needs of an individual. Clinical research in TBI is
particularly challenging due to disease heterogeneity, and has been further
hampered by dispersion of efforts with little collaboration between researchers
in acute and post-acute settings, and by research that focuses on isolated
disease mechanisms and tests highly specific neuroprotective agents in
underpowered clinical trials. RCTs generally employ strict enrolment criteria
in order to study the investigational intervention in the *cleanest* setting.
The downside of this approach is that results are only valid in such selected
subpopulations and that generalizability to the real world context is limited.
Indeed, improvements in TBI care have come not from clinical trials, but rather
from observational studies, expert guideline development and meta-analysis of
individual patient data (Maas et al 2012). However, the large scale
international observational studies on TBI in Europe and the USA that underpin
these improvements date back at least 20 years (Rosenfeld et al 2012) and do
not reflect current clinical care.

Recent advances in genomics, advanced neuro-imaging, and biomarker development
provide unparalleled opportunities for refinements in clinical
characterization, offering more accurate disease phenotyping. Improved disease
characterization will aid Precision Medicine, a concept recently enunciated by
the US National Academy of Science (National Research Council 2011). Such
improved characterization and stratification will allow for more targeted
therapies. Further, Comparative effectiveness research (CER) provides a
promising framework to identify best practices and improve outcome after TBI.
CER is the generation and synthesis of evidence that compares the benefits and
harms of alternative methods to prevent, diagnose, treat, and monitor a
clinical condition or to improve the delivery of care. The purpose of CER is to
assist consumers, clinicians, purchasers, and policy makers to make informed
decisions that will improve health care at both the individual and population
levels (Institute of Medicine 2009).

A basic concept of CER is to study differences in care and outcome in
observational studies, thus turning natural variability into an asset. In
CENTER-TBI, we will exploit the existing heterogeneity in structure, process
and outcome to compare treatments and interventions that are standard practice
in some centres and countries but not in others. Natural links exist between
CER and individualized approaches, since CER aims to identify the best
treatment for the individual patient, with a specific type of injury, severity,
co-morbidities and other aspects that determine optimal treatment. We see a
great potential for CER in TBI because of various unique features: First, there
are large between-centre and between-country differences in both outcome and
management. Second, robust risk adjustment models have been developed
specifically for TBI, providing the possibility to adjust for patient
characteristics that affect outcome. Third, advanced statistical models,
including random effect models, are available to analyze differences between
centres.


2. Concept of CENTER-TBI

The basic concept of this project is to exploit the existing heterogeneity in
biology, care and outcome of TBI patients to discover underlying
pathophysiology, to refine characterisation, and to identify effective clinical
interventions. The key driver of our research plan is to collect data from a
large number of European centres and sufficiently large cohort to enable CER
analyses of differences in clinical care and management pathways in TBI. We
will conduct a prospective longitudinal non-randomized observational study,
recruiting a large core cohort of 5400 patients across the severity spectrum in
TBI at ~80 sites from 21 countries over 18 months (the CENTER-TBI Core Study).
We will follow their progress through the disease course with detailed data
collection up to 2 years post-injury for the most severely injured patients,
thus bridging the acute and post-acute phases. The CENTER-TBI population will
be a unique and well characterized resource, accessible for longer term follow
up with continued funding.

We will characterize centres with regard to their structural profile in order
to explore effects of organizational aspects. Data collection in this large
multinational study will be based upon the common data elements (CDEs), thus
providing evidence context for further refinement and updating of the CDEs in
an international setting, which will inform global standardization of data
collection in TBI. The database structure will be compatible with FITBIR
(Federal Interagency Traumatic Brain Injury Research). We will create and
maintain well curated biorepositories for analysis by the participants and to
provide for legacy research with future new methodologies or longer follow up
of outcome (supported by future grant funding). The core cohort will be
underpinned by comparison with a larger registry (the CENTER-TBI registry:
n=15,000-25,000) based on pragmatic data collection of all patients with TBI
seen in participating centres (to establish the internal generalizability of
our study), and by comparison with national trauma registries (to establish the
external generalizability of our findings).
The integrated results of the project will be brought together in a process of
translational outputs. We aim for real world approaches to translating research
outputs into practical information for patients, healthcare professionals and
policy makers. We will develop and sustain an international TBI knowledge
community that integrates results of the project with high quality 'living
evidence reviews' of the current state of knowledge, aiming to continuously
provide evidence to underpin guidelines and treatment recommendations.
The impact of CENTER-TBI will be enhanced by international collaborations
within and beyond InTBIR. TBI is a global problem and requires a global
approach. The CENTER-TBI database and repositories will be an invaluable
resource for further research which we wish to encourage.

Data sharing policies, providing open access, modelled on the Alzheimer*s
Disease Neuro-imaging Initiative (ADNI) concept, will aim to broaden access to
the data, encourage academic productivity, and accelerate outputs. CENTER-TBI
participants and investigators will have equal access rights to the data.

Our global aims 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.

Specific aims
1. To collect high quality clinical and epidemiological data with repositories
for neuro-imaging, DNA, and serum from patients with TBI.
2. To refine and improve outcome assessment and develop health utility indices
for TBI.
3. To develop multidimensional approaches to characterisation and prediction of
TBI.
4. To define patient profiles which predict efficacy of specific interventions
(*Precision Medicine*).
5. To develop performance indicators for quality assurance and quality
improvement in TBI care.
6. To validate the common data elements (CDEs) for broader use in international
settings.
7. To develop an open source database compatible with FITBIR.
8. To intensify networking activities and international collaborations in TBI.
9. 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.
10. To develop a *knowledge commons* for TBI, integrating CENTER-TBI outputs
into systematic reviews.

4.1 Statement of study design
Longitudinal prospective observational cohort study.

4.2 Subject groups
The study will consist of 2 parts: CENTER-TBI core data study (n=5400) and
CENTER-TBI registry (n=15,000-25,000).

The CENTER-TBI core data collection will be stratified upon enrolment into 3
clinical groups differentiated by clinical care path:
- ER stratum: patients evaluated in the ER and discharged (n=1800)
- Admission stratum: patients admitted to the hospital but not to ICU (n=1800)
- ICU stratum: patients admitted directly from ER or other hospital to the ICU
(n=1800)

We aim for an equal balance in numbers between the strata: approximately 1800
patients per stratum.

THE CENTER-TBI registry will serve 2 important purposes: 1) assessing
representativeness of the CENTER-TBI core study and 2) providing opportunities
for comparative effectiveness analysis of organization of care. Elementary data
from all patients excluded from the core data collection for whatever reason,
but who do have a clinical diagnosis of TBI and undergo CT scanning will be
recorded in the registry.

4.3 Study sites
Approximately 80 centres across 21 countries from Europe and Israel will
participate in CENTER-TBI. A detailed overview is provided in annex 1. With a
large number of centres participating, it is to be expected that some changes
may occur over the course of the project. Updated information will be provided
on the CENTER-TBI website: www.center-tbi.eu




4.4 Number of subjects

CENTER-TBI core study:
5400 patients differentiated into 3 equal strata of approximately 1800. Balance
in numbers between the strata will be aimed for, but sites will be allowed to
arrange recruitment strategies to best suit their local requirements. We would
anticipate a far larger number of eventual subjects in the ER and Admission
strata than in the ICU stratum. Options for achieving balance would be to limit
the recruitment in the ER and admission strata to certain days per week or
certain periods of time. It would be essential to maintain balance of
recruitment across the days of the week.

A maximum cap of enrolment will be implemented per centre in order to prevent
overrepresentation. The cap is currently fixed at a maximum of 100 patients per
stratum with a total number per centre of no more than 250.

CENTER-TBI registry:
No target recruitment number has been set for the CENTER-TBI registry. We
anticipate inclusion of approximately 15.000 to 25.000 subjects.

4.5 Sample size calculation and planned statistical analyses

The 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-country
heterogeneity as identified in previous research (expressed by variance
parameter from a random effects model, Tau^2 of 0.431)
* 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 require somewhat larger odds ratios
in each of the three 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%.

The planned analyses are described in detail in the description of work for
CENTER-TBI as approved by the European Commission.
Statistical analyses for the Comparative Effectiveness Research (CER) questions
will primarily apply random effects modelling, in which center is included at
the higher level, and patients are considered clustered within centers. In some
analyses, higher levels of clustering will also be considered, e.g. country, or
European region; or lower levels, e.g. physicians within hospitals. Confounding
factors as measured at the individual patient and/or center level, will be
considered extensively, and will be targeted to the specific research question.
Statistical analyses for better characterization of TBI will be exploratory,
aiming to better understand the complexity of the disease and to discover new
associations. In addition to standard statistical descriptive and inferential
techniques, we will also employ novel machine learning techniques as
appropriate.
Prognostic analyses will consider a range of variables, including genetic,
demographic and clinical data, physiological signals, imaging results, and
biomarkers as predictors of early endpoints and physiologic derangement (e.g.
raised ICP), and late outcome, including mortality, functional outcome, quality
of life and neuropsychological performance. Previously and newly developed
prediction models will be validated by comparison of observed to predicted
outcome risks, with predictive performance summarized by measures for model
fit, discrimination, and calibration.

4.6 Study Duration
Recruitment for CENTER-TBI is planned over an 18 months period with a maximum
follow-up duration of 2 years. Recruitment will end when the target numbers are
reached. In the event of slower recruitment, the recruitment period may be
extended.
4.7 Inclusion * exclusion criteria
CENTER-TBI core study:
Main criteria for inclusion:
1. Clinical diagnosis of TBI
2. Clinical indication for CT scan
3. Presentation within 24 hours of injury
4. Informed consent obtained according to local and national requirements

Exclusion criteria:
Severe pre-existing neurological disorder that would confound outcome
assessments

CENTER-TBI registry:
Main criteria for inclusion:

1. Clinical diagnosis of TBI
2. Clinical indication for CT scan

No other inclusion or exclusion criteria apply for the Registry dataset.

Foreseeable risks and their minimization
No therapeutic interventions will take place in the context of the
observational studies. Diagnostic interventions include blood sampling, outcome
assessments and in selected sites MR imaging, HR ICU monitoring and extended
blood sampling. The potential risks to the subject are minimal across all
domains of data collection.

Clinical. Study data will be entered into eCRFs using secure, encrypted
connections to the eCRF data. All data will be confidential and stored in
locked areas to which only authorized study personnel have access. Records will
be coded with a GUPI as early as possible so that names and other identifying
information will not be linked to personal or sensitive data, in compliance
with existing regulations. In addition, subjects and their families will be
informed that participation is completely voluntary, that they may decline
response to any questions they may find distressing, and that they may withdraw
from the study at any time, all without jeopardizing medical treatment to which
they are otherwise entitled.

Biospecimens. The blood sample will be drawn from an arterial or (central)
venous catheter placed as a part of standard care for those patients
consented while in the ICU. Those patients consented on the ward or emergency
room will need to undergo a blood draw and may experience the discomfort
associated with a needle stick and may suffer bruising at the site of the
needle stick. This will be minimized as much as possible. No more than two
venepuncture attempts will take place. Whenever possible, blood draws will be
combined with those of routine clinical care. The additional blood draws
performed for purposes of the study will not exceed 40 ml upon presentation, 75
ml during the acute clinical course (only ICU stratum), and no more than 30 ml
over a 2-year follow up period.

Genetic Research. The highest degree of privacy protection is required with
regard to genetic data, as a possibility exists that this information could
affect one*s ability to be insured, employed, future decisions regarding
children, or family relationships. All data will be de-identified, and results
only coded by the GUPI code. All analyses will be performed centrally after
completion of recruitment. The information linking the GUPI code to patient
data will be retained locally at study sites, and will be stored in secure
areas to which only authorized study personnel have access. Given the delay
between sample collection and genotyping, the research (rather than clinical)
standards used for genotyping, and the enormous variation in the facilities
available for counselling and follow up, we have elected not to make incidental
genetic results available to participants.


If any unexpected findings are identified that may be clinically significant,
we require that local PIs follow local policy for review, reporting and
counselling. Where the data are from a patient, and pertain to TBI, we
recommend that the clinician caring for the patient should be made aware of the
findings. Non-TBI related findings (e.g. incidental developmental
abnormalities, or a intracranial tumour discovered on MR) in patients or
incidental findings in healthy controls should be dealt with based on locally
agreed protocols * in many centres the arrangement is that the participant is
counselled by the Site PI and recommended to seek medical care from their
primary care physician.

Outcomes. Some of the questionnaire assessments deal with issues such as
emotional distress, and these have all been used in previous studies. There are
no known risks carried by any of the assessments, including items concerning
self-harm. This will be explained to participants both orally and in the
consent document. Further, only trained study personnel will administer such
interviews and questionnaires. All participants will be given information
concerning local sources of help for common forms of distress after TBI. If a
participant gives any indication that they might self-harm, it will be
documented in the research record and the research personnel will notify the
medical staff according to local clinical policies and procedures.


Potential benefits
Health Care Professionals: We anticipate that our study will transform
characterization of TBI, and improve detection and understanding of disease
processes, mirroring the recommendations of the National Academy of Science
(NAS) on the importance of developing a new taxonomy in the context of
Precision Medicine. The expected impact of CENTER-TBI is displayed in figure
3.2, adapted from the NAS report. We expect that improved disease
characterization and identification of best practices will lead to therapies
that are better targeted and more individually oriented (Precision
Medicine).Knowledge gained from the CER analyses will be integrated with
systematic reviews of the existing literature to produce improved and
harmonized clinical guidelines, facilitating constant improvement by the
clinical neurotrauma community.

Policymakers: Insight into current epidemiological patterns of TBI across
Member States will inform prevention campaigns, targeted to needs at national
levels. Our focus on the impact of systems of care and organizational aspects
of care delivery could yield substantial benefits: for example introduction of
the UK NICE Guidelines for TBI management was associated with a 12% reduction
in TBI mortality (Fuller et al 2011). More efficient and targeted care and
improved outcome will reduce costs. New performance indicators and improved
prognostic models will facilitate benchmarking and assessments of quality of
care.

In summary, 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
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 research.