Mise au point d`un outil de prédiction de l`avenir

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Mise au point d`un outil de prédiction de l`avenir
RESEARCH PROTOCOL
« THE USE OF MRI DERIVED BIOMARKERS TO PREDICT CONSCIOUSNESS RECOVERY IN
TBI, SAH, ICH AND HIE PATIENTS »
Principal investigator and Coordinator:
Pr. Louis PUYBASSET
Neurosurgical Intensive Care Unit, Department of Anaesthesia-Reanimation.
Hospital of Pitiè-Salpêtrière, 47-83, Boulevard de l’hôpital; 75013, Paris, France.
Ground Line: (33) 1 42 16 33 85; Secretary: (33) 1 42 16 33 71
Beep 38-336 by (33) the 1 42 16 00 00, Mobile (33) 6 63 25 95 10
Fax: (33) 1 42 16 33 70 or (33) 1 42 16 22 69
Email: [email protected]
Sponsor:
Protocol being accepted by the Ethics Committee (Paris Pitié-Salpêtrière) 30/05/2006
1
Index
1
2
3
4
5
Introduction, research justification, attended results and perspectives ......... 6
Objectives........................................................................................................ 7
2.1
Main hypothesis ...................................................................................... 7
2.2
Primary Objective.................................................................................... 7
2.3
Secondary Objectives .............................................................................. 7
2.3.1 Clinical Outcome by additional clinical scales ......................................... 7
2.3.2 Other sequences.................................................................................. 7
2.3.3 Further time-points evaluations ............................................................ 7
Experimental plan ........................................................................................... 7
3.1
Choice and justification ........................................................................... 7
3.2
Inclusion criteria ..................................................................................... 8
3.2.1 Inclusion criteria .................................................................................. 8
3.2.2 Non inclusion criteria ........................................................................... 9
3.3
Statistical Analysis and justification for the number of patients .................. 9
3.4
Protocol of MRI exploration ..................................................................... 9
3.5
Data analysis ........................................................................................ 12
3.5.1 DTI ................................................................................................... 12
3.5.2 MRS .................................................................................................. 14
3.6
Estimated total duration of the study...................................................... 15
3.7
Study drop-outs .................................................................................... 15
Management of the serious adverse events .................................................. 15
4.1
4.2
Definitions ............................................................................................ 15
Collection of serious adverse events ....................................................... 15
5.1
5.2
5.3
5.4
Sponsor Responsibilities ........................................................................ 16
Documentations for the research and obligations of the investigators ....... 16
Quality control and Quality assurance ..................................................... 16
Personal Data confidentiality .................................................................. 16
Lawful and general aspects ........................................................................... 16
Appendix 1 : Steering committee ......................................................................... 18
Appendix 2 : French Investigational centres ........................................................ 18
2
Summary
Predicting long-term outcome of critical neurological conditions such as traumatic brain injury
(TBI), aneurysmal subarachnoid hemorrhage (aSAH), intraparenchymal hematoma (ICH) and
severe hypoxic-ischemic encephalopathy (HIE) at the sub-acute phase while the patient is
still in an acute care setting remains complex, inadequate and unsatisfactory. This leads to a
wide array of patient management difficulties and may lead to under- or over-aggressive
patient care, inaccurate expectations on the part of relatives, and significant financial burden
for the healthcare system. Advanced MRI techniques, namely DTI and MRS, providing MRIderived biomarkers, offer a unique opportunity to improve our prognostication tools of the
disorders of consciousness (DOC). However, this requires first to standardize those MRI
acquisitions among all centers involved with such patients before these centers define their
own local settings and secondly to be able to share the data on a large scale to provide
sufficient power for outcome prediction per pathology.
A multi-center study aimed at defining the algorithms predicting clinical outcome at one
year after severe TBI, aSAH, ICH or HIE was launched in 2006. This study was performed
under the direction of Louis Puybasset and Damien Galanaud at the Pitié-Salpêtrière
Hospital in Paris and was conducted in 12 centers in France, Belgium and Switzerland. So
far, the study has enrolled 80 controls and 330 patients. As a mean, MRI were performed at
22 ± 11 d after the ictus while the patients are still in ICU and mechanically ventilated. The
experience of this French database constitutes the basis for the projected European cohort.
The French cohort will allow us to define the first predictive algorithms using quantitative
biomarkers extracted from DTI and MRS combined with covariables such as age, etiology of
the disorder of consciousness, initial Glasgow Coma Scale score, clinical status at the time of
the MRI and patient co-morbidities to predict the 1 year outcome evaluated according to
two groups: unfavourable (death, VS, MCS) or favourable outcome (above MCS). These
algorithms will be validated and improved further on a larger scale using the European data.
For the prediction of an unfavourable outcome, specificity will be clearly privileged at
detriment of sensitivity.
Objective
The aim of this project is to build up a consortium of EU hospitals and universities that, in
conjunction with their international counterparts (USA and Australia mainly) will prospectively
collect clinical and MRI data on patients with DOC following the four diseases stated above
(TBI, aSAH, ICH, HIE). This information will be entered into a shared repository. The CRF,
the MRI protocol, the common data elements and the serial time points for data collection
will be standardized across all institutions and at the international level. In a subset of
centers, a blood sample for DNA analysis will be performed and centralized in Paris (Pr
Cambien Laboratory) for latter pangenomic analysis.
Data will be shared in order to design a web-based, public, open source expert system for
predicting outcome at 1-year in severe TBI, SAH, ICH and HIE. A specific algorithm will be
designed per pathology.
Any new center willing to use the system will be asked to send the MRI of 10 healthy
volunteers to calibrate the MRI machine. A further group of 20 patients suffering from either
TBI, aSAH, ICH, HIE and having the inclusion criteria will be demanded. Doctors in charge of
these patients will be blinded as regard to the DTI and MRS results. This will allow to
ascertain that this given center has the technical ability to perform the MRI first and secondly
to feed the base with new patients allowing a better statistical precision for outcome
prediction.
3
Design
Multicentric prospective cohort with consecutive inclusions within the European neuroICU
and ICU networks.
Inclusion criteria : Adult affiliated to the national social security system; Hospitalized in ICU
and requiring artificial ventilation following TBI, aSAH, ICH or HIE; with an acute disorder of
consciousness (DOC) defined as a patient not responding to simple orders at least 5 days
after the event; receiving an amount of sedatives not being able to explain the disorder of
consciousness; having a standardized intracranial pressure (ICP ≤ 20 mmHg after 30 min of
supine position) and in absence of severe hemodynamic or respiratory failure so that the
MRI does not represent any additional danger; signed informed consent form.
Data acquired
Clinical
Characteristics of the admission; Clinical data summarizing neuroICU events and treatments,
as well as in regular ward and rehabilitation facilities; Clinical status at 6 months and 1 year
as assessed by GOS, DRS, modified Rankin and GOSE. This evaluation will be under the
responsibility of the investigator of each centre.
All data will be entered in a web site in English (nearly finalized at the present time).
MRI
The MR examination must include 3DT1-weighted, T2, FLAIR, T2* or SWI, diffusion tensor
imaging, MR spectroscopy on the pons and chemical shift imaging (CSI) at the level of the
basal ganglia. In selected participating centers, a BOLD fMRI acquisition (resting state)
should also be performed. MRI will be carried out at least 5 days after the event for HIE, 7
days for TBI and ICH and for aSAH. In addition, 10 healthy volunteers will be recruited at
each of the participating centers prior to the inclusion of patients.
The objective of these explorations is to obtain standards for the multimodal MRI.
Genetic
One blood sample for further genetic analysis
Data analysis
MRI quantitative analysis will be carried out in a centralized way according to automatic
computerized analysis already under development for both DTI and MRS data. Statistics will
include clinical co-variables.
Pangenomic genetic analysis will be performed on a centralized manner.
Sample size
Based on the results of the French multicentric study (TBI group), the number of patients to
prospectively recruit in order to obtain 99% specificity to predict an unfavourable outcome at
one year with a statistical power of 90% is 192 per etiology. Furthermore, an incidence of 20
% of in-ICU deaths is expected (these patients might be removed of the base to avoid the
so-called “self fulfilling prophecy”). In addition, 20% of the included patients are expected to
be lost to follow-up within 1 year or to have incomplete datasets. Therefore, the total
4
number of patients to be enrolled per pathology tested is 360 (i.e. TBI, SAH, ICH and HIE)
resulting in 1280 patients overall. Based on the multicenter experience, we expect to acquire
this number of patients in 3 years, completing clinical follow-up by the 4th year.
Expected results
The final goal of the project will be the development of a web-based, public, open source
expert system for predicting unfavorable 1-year neurological outcome (death, VS, MCS) of
patients presenting a disorder of consciousness following TBI, SAH, ICH and HIE, with near
100% specificity. This system will allow any center worldwide to upload images and clinical
information and generate probabilistic outcome maps at 12 months after the injury while the
patient is still in the ICU. This will allow, not only to provide a more accurate information to
the families but also to better titrate care, thus allowing an improved allocation of limited
resources.
5
1 Introduction, research justification, attended results and perspectives
In an acute and sub-acute setting, predicting long-term outcome of critical neurological
conditions such as traumatic brain injury (TBI), aneurismal subarachnoid hemorrhage
(aSAH), intraparenchymal hematoma (ICH) and severe hypoxic-ischemic encephalopathy
(HIE) remains complex, inadequate and unsatisfactory. This leads to a wide array of patient
management difficulties and may lead to under- or over-aggressive patient care, inaccurate
expectations on the part of relatives, and significant financial burden for the healthcare
system.
Advanced MRI techniques offer a unique window into the pathophysiology of disorders of
consciousness (DOC). It is known that the presence of lesions in critical areas such as the
brainstem is suggestive of poor prognosis. Recent advances in diffusion tensor imaging (DTI)
and MR spectroscopy (MRS) provide the ability to detect subtle anatomical and metabolic
changes and their relationship to functional outcomes. MRI scans, performed in patients with
DOC as early as two weeks after injury, can predict neurological outcomes with a high
degree of specificity and be integrated in the clinical decision-making process.
The relatively small sample sizes and variability in the neuroimaging protocol limit the
practical use of these preliminary data.
A multi-center study, funded by the French Health Ministry ("Projet Hospitalier de Recherche
Clinique,” 2005) in 12 centers in France, Belgium and Switzerland was launched in 2006.
Under the direction of Louis Puybasset (Neurosurgical Intensive Care Unit) and Damien
Galanaud (Neuroradiology) at the Pitié-Salpêtrière Hospital in Paris, this study aimed to
develop an expert system to predict the outcome at 1 year following severe TBI, aSAH, ICH
or HIE. So far, this study has enrolled 330 patients among whom 170 TBI patients. 80
controls were also scanned using the same MRI protocol. The data, which are still being
analyzed, have already shown the feasibility of this approach in a multicentric setting. We
have already developed a tool to correct inter centers variability in DTI acquisitions,
enabling a good reproducibility of the data between the centers.
This experience of the French database constitutes the basis for the European cohort and
the description of the first predictive algorithms. The aim of this project is to build a
consortium of EU hospitals and universities that, in conjunction with their international
counterparts (USA and Australia mainly), will prospectively collect clinical and MRI data on
patients with DOC. This information will be entered into a shared repository. The CRF, the
MRI protocol, the common data elements and the serial time points for data collection will be
standardized across all institutions. This database will enable the development of powerful
tools and expert systems in patients with DOC outcome prediction. In addition, it will provide
new insights on the anatomical and functional basis of patients with disorder of
consciousness emergence and recovery.
Based on preliminary results, we estimate that 1280 patients will be needed to reach
sufficient power to discriminate between favorable and unfavorable outcomes defined as
death, VS and MCS. For most patients, Glasgow Outcome Scale (GOS), Disability Rating
scale (DRS), modified Rankin (mRankin) and Glasgow Outcome Scale Extended (GOSE) will
be determined by a phone interview at 6 months and one year.
To clearly establish the diagnosis of vegetative state (VS) and minimally conscious (MCS)
patients, an on-site clinical evaluation will be performed for patients whom GOSE at 1 year
6
corresponds to VS (GOSE 2), Lower Severe disability (GOSE 3) or Upper Severe Disability
(GOSE 4).
The final goal of this project will be the development of an open source expert system for
predicting unfavorable long-term neurological outcome of patients presenting a disorder of
consciousness following TBI, SAH, ICH and HIE, with near 100% specificity. This system will
allow any center worldwide to upload images and clinical information and generate
probabilistic outcome maps at 12 months after the injury.
2 Objectives
2.1
Main hypothesis
MRI biomarkers extracted from DTI and MRS combined with clinical data predict, in a
reliable and reproducible way, the neurological outcome at 1 year of patients presenting a
disorder of consciousness at the acute phase after TBI, SAH, ICH and HIE.
2.2
Primary Objective
To define algorithms using quantitative biomarkers extracted from DTI and MRS combined
with clinical covariables to predict an unfavourable outcome (death, VS, MCS) with a
specificity close to 100%.
2.3
Secondary Objectives
2.3.1
Clinical Outcome by additional clinical scales
Relevance of the algorithms to predict the clinical outcome at 1 year assessed by the
Glasgow Outcome scale (GOS), the Glasgow Outcome Scale Extended version (GOSE),
the Rankin score (mRankin), the Disability Rating Scale (DRS).
2.3.2
Other sequences
In a subset of centers, resting-state functional MRI and arterial spin labelling sequences
will be performed and introduced in the model.
2.3.3
Further time-points evaluations
In a subset of centers, repeated imaging will be performed to study mechanisms of
neuronal plasticity after severe TBI, aSAH, ICH or HIE. This will be correlated to genetic
analysis.
3 Experimental plan
3.1
Choice and justification
Multicentric prospective cohort with consecutive inclusions within the European neuroICU
and ICU networks. Approximately, 1280 patients will be included during a period of 3 years
and followed during their hospitalization period in the intensive care unit, regular ward and
rehabilitation facilities of the investigational centers for the year following the event (1 more
year).
All data will be acquired on a web based system nearly already functional.
In practice, the study will proceed in 5 stages:
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1. Inclusion. This stage consists in checking the criteria of inclusion and non-inclusion, and
collecting information regarding:

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Characteristics of the admission in the primary and secondary hospital, if applicable.
Medical, surgical and toxicological history.
Nature of the cerebral lesion.
Initial clinical and radiological assessment (e.g. severity on scanner).
Possible emergency surgical procedures (neurosurgical and non-neurosurgical).
First clinical events.
Clinical status at the time of the realization of the MRI.
Signature of informed consent.
Blood sample for genetic analysis in a subgroup of centers
2. MRI Examination. The MRI will be carried out at least 5 days after the event for HIE, 7
days for TBI, ICH and for aSAH (these different delays are due to the differences in the
mechanisms of brain injury in these 4 conditions). For patients, MRI will be performed under
mechanical ventilation, sedation, monitoring and under the supervision of a qualified
anaesthesiologist-intensivist. CDs containing the information of the MRI will be shipped to
the coordination centre. Later on, a push and play system allowing the automatic
transmission of anonymized MRI raw data will be installed in each participating center.
3. MRI Quantitative analysis. It will be carried out in a centralized way according to
computerized analysis already developed.
4. Clinical data summarizing neuroICU events and treatments, as well as in regular ward and
rehabilitation facilities
5. Clinical status at 6 months and 1 year as assessed by GOS, DRS, modified Rankin and
GOSE. This evaluation will be under the responsibility of the investigator of each centre. For
most patients, GOS, DRS, mRankin and GOSE will be determined by phone interview at 6
months and one year. To clearly establish the diagnosis of vegetative state (VS) and
minimally conscious (MCS) patients, an on-site clinical evaluation will be performed for
patients whom GOSE at 1 year corresponds to VS (GOSE 2), Lower Severe disability (GOSE
3) or Upper Severe Disability (GOSE 4).
In addition, 10 healthy controls will be recruited at each of the participating centers prior to
the inclusion of patients. The objective of these explorations is to obtain standards for the
multimodal MRI. These examinations, entirely non-invasive will be carried out without
injection of product of contrast.
The healthy volunteers will be recruited by respecting the same contraindications as for
patients and the law governing healthy volunteers’ studies (absence of contraindication to
the MRI, absence of pre-existing brain pathology, subjects profiting from social health
insurance). The inclusion visit and the signature of the informed consent form will be carried
out by the investigators.
3.2
Inclusion criteria
3.2.1



Inclusion criteria
Adult affiliated to the national social security system
Hospitalized in ICU and requiring artificial ventilation following TBI, aSAH,
ICH or HIE.
With an acute disorder of consciousness (DOC) defined as a patient not
responding to simple orders at least 5 days after the event.
8



Receiving an amount of sedatives not being able to explain the disorder of
consciousness.
Having a standardized intracranial pressure (ICP ≤ 20 mmHg after 30 min of
supine position) and in absence of severe hemodynamic* or respiratory
failure** so that the MRI does not represent any additional danger.
Informed signed consent form
*Severe hemodynamic failure is defined as a circulatory state requiring norepinephrine or
epinephrine > 3 mg/h and/or Dobutamine > 10 µg/kg/min
** Severe respiratory failure is defined as the need for a FiO2 > 60% and a positive
expiratory pressure > 10 cmH2O to obtain a PaO2 above 80 mmHg.
3.2.2
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3.3
Non inclusion criteria
Cranial trauma of ballistic origin
Disorder of consciousness (DOC) of infectious or toxic origin
Disorder of consciousness (DOC) explained by sedation
MRI Contraindication (pace maker, or medical material not MRI compatible)
Positive postural test defined as an ICP > 20 mmHg after 30 min of supine
position
Severe hemodynamic failure
Severe respiratory failure
Life threatening extra-cerebral lesions
Patient presenting a severe compromise of a major function altering the vital
outcome during the acute phase
Patient presenting a previous neurological lesion with any handicap altering
the clinical outcome
Patient protected by the law (under supervision or trusteeship)
Refusal of the family
Statistical Analysis and justification for the number of patients
Based on the results of the French multicentric study (TBI group), the number of patients to
prospectively recruit in order to obtain 99% specificity to predict an unfavourable outcome
at one year with a statistical power of 90% is 192 per etiology.
Furthermore, an incidence of 20 % of in-ICU deathsa is expected. In addition, 20% of the
included patients are expected to be lost to follow-up within 1 year or to have incomplete
datasets. Therefore, the total number of patients to be enrolled per pathology tested is 360
(i.e. TBI, SAH, ICH and HIE) resulting in 1280 patients.
Based on the multicenter experience, we expect to acquire this number of patients in 3
years, completing clinical follow-up by the 4th year.
3.4
Protocol of MRI exploration
MR acquisitions can be performed on either a 1.5T or a 3T unit (3T should be preferred
whenever possible), in the presence of a neuroradiologist and an anaesthetist from the ICU
a
The expert system will be designed with and without the in-ICU death. Not taking into account in-ICU
death is added as a guaranty to avoid the so-called “self fulfilling prophecy” bias.
9
in a sedated, intubated, ventilated and monitored patient (non-invasive ECG, PaO2, SaO2,
and ETCO2).
All MRIs must be acquired always on the same MR unit. The same head coil must also be
used for all patients and controls.
The MR examination must include 3DT1-weighted, T2, FLAIR, T2* or SWI, diffusion tensor
imaging, MR spectroscopy on the pons and chemical shift imaging (CSI) at the level of the
basal ganglia. In selected participating centers, a BOLD fMRI acquisition (resting state)
should also be performed if possibleb.
If axial T2 and FLAIR acquisitions are performed, the bicallosal landmarks should be used
(see figure 1). If 3D sequences are preferred, the FLAIR should be reconstructed in the
bicallosal plane to position the CSI spectroscopic acquisition.
Figure 1: standard exploration plane. Do not forget to correct the rotation of the head on the
axial plane.
MR protocol
Conventional sequences
- an axial (or 3D) FLAIR acquisition. Standard parameters for axial acquisition are: 3 mm
thickness, 256x256 matrix. Maximal FOV = 28 cm
- an axial (or 3D) T2 acquisition. parameters for axial acquisition are: 2 mm thickness,
256x256 matrix. Maximal FOV = 28 cm. This acquisition may not cover the whole brain but
should extend at least from the junction between the pons and medulla oblongata to the
summit of the corpus callosum
- an axial T2* or SWI acquisition
- a 3D T1 acquisition using the IR-FSPGR (GE) or MPR (Siemens and Philips) sequence.
The maximum size of the voxel should be 1.2 mm, isotropic. The acquisition plane is the one
generally used on the MR unit
- a sagittal T2-weighted acquisition covering the brainstem. This sequence is only used to
position the single voxel acquisition and can be skipped if a sagittal T1 or T2 reconstructed
acquisition can be used to program this sequence. The sagittal T2 acquisition must be tilted
to put the pons as vertical as possible.
b
For additional information, you can contact
Damien Galanaud
Department of Neuroradiology, Pitié Salpêtrière Hospital
47 Boulevard de l’Hôpital F-75013 Paris, France
Tel: +33 1 42 16 35 01
[email protected]
10
MR spectroscopy
- a single voxel acquisition (SVS) on the pons. The voxel should be positioned on the
2/3 posterior part of the pons, covering all its height (figure 2). Thickness 15mm, frequency
direction S/I, PRESS acquisition mode, TR=1500 ms, TE=135 ms, 4 acquisitions without
water suppression and 96 acquisitions with water suppression.
Figure 2: positioning of the SVS acquisition on the pons. The acquisition is positioned on the
sagittal acquisition. The axial acquisition it used to verify that the voxel is correctly positioned
laterally. Partial volume is acceptable on the 4th ventricle but should be avoided on the clivus
(because it leads to unacceptable spectral quality) and the cerebellum (because of markedly
different metabolic ratios on this structure).
- an axial CSI acquisition, performed at the level of the basal ganglia, with a 15 mm slice
thickness. PRESS acquisition mode, TR=1500 ms, TE=135 ms, FOV 24 cm, 18x18 matrix.
This sequence should be positioned on the FLAIR sequence, either native or reconstructed
on the bicallosal plane (figure 3). This acquisition should also be performed with and without
water suppression.
Figure 3: positioning of the CSI acquisition, with outer volume saturations (OVS). On GE
magnets, these OVS are automatically positioned and no further steps are required. On
Philips and Siemens magnets, they must be manually positioned.
General considerations on MRS acquisitions:
11
2 to 4 acquisitions without water suppression should also be performed since the
signal of the water will be used in some post processing systems. This is donned
automatically on GE unit, and this information is embedded in the raw data files. These
sequences must be programmed separately on Siemens and Philips units
The raw data of the MR spectroscopy must be archived. 4 raw data files should thus
be saved on Philips and Siemens systems (Pons SVS with water suppression, Pons SVS
without water suppression, CSI with water suppression, CSI without water suppression) and
2 on GE units (Pons SVS, CSI).
Diffusion tensor imaging
Acquisition is performed in a strict axial plane (perpendicular to the axis of the magnet). The
value of B is 1000 s/mm2. The parameters of the DTI acquisitions can be adjusted, according
to the possibilities of each center. The minimal requirements for the sequence are:
- a voxel at most 3 mm, isotropic
- at least 12 directions
The optimal parameters for the DTI acquisitions are those performed in reference centers
in France and Belgium.
- 64 directions
- 2 mm isotropic
Optional
BOLD fMRI acquisition
The purpose of this acquisition is to evaluate the destructuration of the default mode
network. This acquisition is optional, and will be performed in a sub-group centers. The MRI
parameters are:
- strict axial plane perpendicular to the axis of the magnet
- TR=2400 ms, TE minimal, Frequency R/L, 250 averages
- 64x64 matrix, 3mm thickness, 192x192 FOV
In addition, sedation must be as far as possible standardized for these patients
during the procedure.
Amount of sedative drugs, FiO2, respiratory and cardiac frequency, and pulse saturometry at
the time of the MRI must be recorded into the eCRF.
3.5
Data analysis
3.5.1
DTI
The FA measures will be extracted in a limited number of areas (17 Regions of InterestROIs) covering most of the major white matter pathways and whose functional role is known
(see figure 4).
12
Figure 4: the 17 ROIs considered. These regions were selected on the skeleton of the main
lines of white matter from the atlas of white matter in MRI [Mori et al., 2005]
The determination of the FA of these 17 ROIs will be automatically performed by a software
under development ("TBISoft"_see figure 5).
Figure 5. Main window and display examples of software TBISoft
13
3.5.2
MRS
The ratios NAA/Cr, NAA/S, Cho/S (S=NAA+Cr+Cho) and Cho/Cr will be determined
automatically at the level of the protuberance (on monovoxel acquisition) and 9 localizations
of the CSI, i.e. the occipital-parietal cortex, the occipital-parietal white substance (right and
left side), the lenticular cores (right and left side), thalamii (right and left side), and insula
(right and left side,see figure 6 determined in an healthy volunteer).
Figure 6: localization and aspect in MRS of the studied voxels.
14
3.6
Estimated total duration of the study
The total duration of the study is 4 years, with one period of 36 months of inclusion, with an
evaluation at 1 year for all included patients.
3.7
Study drop-outs
The participation of the patients in the study will not interfere with their usual standard of
care. The patient recovering from the DOC or his/her family, will be able to request at any
moment the withdrawal from the study.
The MRI will be carried out only under the specified conditions noted above. Any event
occurring during the realization of the MRI will have to be notified to the coordinating centre
at the time of the transmission of the data of the MRI.
Those patients who will die after their inclusion in the study of a pure extra-neurological
cause will be excluded from the statistical analysis (drop-out). Each decision to exclude
deaths of purely extra-neurological causes of the study will have to be made by the steering
committee.
4 Management of the serious adverse events
4.1
Definitions
An adverse event is defined like any adverse event undergone during the realization of the
MRI, whether it is related or not to the performance of it or the studied strategy.
A serious adverse event is an adverse event observed at the time of the realization of the
MRI which has been able to contribute to the occurrence of
-
Death
Life threatening setting
Inpatient hospitalization or prolongation of existing hospitalization
Significant/persistent sequellae
Or
the occurrence of any other event not corresponding to the qualifications mentioned above,
but being considered as “potentially serious” in particular, certain biological anomalies or
event related/relevant according to the investigators judgment.
All the serious adverse events (SAE) will have to be the subject of a report on the form
“Serious Adverse Event Report” which is within the electronic case report form; the form
must be completed on line, be printed under pdf format, be signed by the investigator
declaring the AE and be faxed to the European health authorities.
The investigator will have, for each reported event, to pronounce on the “Serious Adverse
Events Report” his medical opinion on the relationship existing between the occurrence of
the side effect and the protocol.
4.2
Collection of serious adverse events
Any adverse event will be registered in the case report form corresponding evaluation. The
absence of any adverse event will be also registered.
15
5 Lawful and general aspects
In France, this protocol has been considered according to law of research of Huriet. In
agreement with the L.1123-6 article of the French Code of Health, the protocol of research
has been subjected at a Consultative Committee for the Protection of the People in
Biomedical Research (Ethical Committee) of Ile -de France (IDF), after sponsor agreement
(with the certificate of insurance).
Each site will be responsible for the submission to its own ethical committee.
The final approval from this committee will be notified in accordance to the proper authority
by the sponsor before the initiation of the study. The investigator will inform the families
and/or close relatives of the aims of the study and his unfolding. The informed consent form
will be signed by the family or the close relative and secondarily by the patient having taken
part in the study.
5.1
Sponsor Responsibilities
To be determined
5.2
Documentations for the research and obligations of the investigators
Before initiating the study, the coordinating investigator will provide to the representative of
the sponsor a copy of his personal curriculum vitae updated and signed and comprising his
record of inscription to the Order of the Doctors, just as all the investigators.
The version of the protocol before ethical committee submission with its appendices will be
signed and accepted jointly by the coordinating investigator and the sponsor. If necessary,
the scientific person in charge will be also signatory.
At the time of each new version of the protocol, made necessary by amendments and/or
requests of the authorities, a new number and date will be allocated and the same
signatures collected.
Each investigator will commit himself to respect the obligations of the law and undertaking
research according to GCP and by respecting the terms of the declaration of Helsinki. For this
matter, a scientific agreement will be obtained and signed (standard template) by each
investigator at each participating centre.
5.3
Quality control and Quality assurance
This research will be framed according to the standard operational procedures' of sponsor.
The course of research in the investigational centres and the standard of practice of the
subjects will be made in accordance with the declaration of Helsinki and the GCPs.
5.4
Personal Data confidentiality
In accordance with the law known as “Data-processing and Freedoms”, the family, the close
relatives and the patients will be informed of the data treated in a nominative and
computerized file and that they will be able to have access to the data relating to them
either by means of the investigator or via the doctor of their choice.
16
The study and its results are the property of the sponsor and the investigators are held,
according to the terms of the Law, with professional secrecy. Any publication concerning the
study and its results requires prior written agreement from the promoter.
17
Appendix 1 : Steering committee
This committee will be in charge of the regular follow-up of the study and will meet at least
2 times per year. The members of the committee are responsible for the evaluation of the
critical events during the study. It will be also charged to evaluate for each patient deceased,
if the cause is due to extra-neurological causes or is secondary in a direct or indirect way to
the cerebral lesion. This evaluation will be carried in double-blind fashion. It will be sovereign
for all the decisions concerning the scientific publication of the results (princeps and
ancillaries studies).
Appendix 2 : French Investigational centres
Paris, France
Hôpital Pitié-Salpêtrière
Pr Louis Puybasset
Unité de NeuroAnesthésie-Réanimation
Département d'Anesthésie-Réanimation.
47-83, Bd de l'hôpital; 75013, Paris, France.
Phone : (33) 1 42 16 33 85; Secretary : (33) 1 42 16 33 71
Beep 38-336 through (33) 1 42 16 00 00
Fax: (33) 1 42 16 33 70 or (33) 1 42 16 22 69
[email protected]
Pr J Chiras et D Dormont
Département de Neuroradiologie
47-83, Bd de l'hôpital
75013, Paris, France.
[email protected]
[email protected]
Lille, France
Pr Benoit Tavernier
Clinique d’Anesthésie-Réanimation
Hopital Roger Sallengro
59037, Cedex Lille
Phone: (33) 3 20 44 62 69
Fax: (33) 3 20 44 64 88
[email protected]
Pr. Jean-Pierre Pruvo,
Service de Neuroradiologie
Hôpital Roger Salengro
CHRU de Lille
59037 Lille Cedex
Phone : (33) 3 20 44 64 68
Fax : (33) 3 20 44 64 88
[email protected]
Lyon, France
18
Dr Frédéric Dailler
Unité de réanimation et de soins intensifs Post-opératoires.
Hôpital Neurologique et neurochirurgical Pierre Wertheimer
59 Boulevard Pinel
69677 BRON CEDEX
Phone secretary: (33) 4 72 35 78 11
Fax : (33) 4 72 35 70 54
[email protected]
Dr Marc Hermier
Dominique Sappey-Marinier.
CERMEP
Hôpital Neurologique et neurochirurgical Pierre Wertheimer
59 Boulevard Pinel
69677 BRON CEDEX
[email protected]
[email protected]
Marseille, France
Professeur Nicolas Bruder
Département d'Anesthésie-Réanimation
CHU Timone, 264 rue St Pierre
13385 Marseille Cedex
Fax : (33) 4 91 38 57 35
[email protected]
Pr Nadine Girard
Service de Neuroradiologie
CHU Timone, 264 rue St Pierre
13385 Marseille Cedex
[email protected]
Rouen, France
Pr Benoit Veber
Département d’Anesthésie - Réanimation chirurgicale
Centre Hospitalier Universitaire de Rouen (CHU)
1 r Germont 76000 Rouen
Phone : (33) 2 32 88 82 92
[email protected]
Dr Emmanuel Gerardin
Service de Neuroradiologie
Centre Hospitalier Universitaire de Rouen (CHU)
1, rue Germont
76000 Rouen
[email protected]
Nancy, France
Dr Gérard Audibert
19
Département d’Anesthésie - Réanimation chirurgicale
Centre Hospitalo-Universitaire de Nancy,
Hôpital Central,
29 avenue du Maréchal de Lattre de Tassigny,
54000 NANCY, France
Phone : (33) 3 83 85 16 84
Fax : (33) 3 83 85 27 02
[email protected]
Pr Serge Bracard
Service de Neuroradiologie
Centre Hospitalo-Universitaire de Nancy,
Hôpital Central,
29 avenue du Maréchal de Lattre de Tassigny,
54000 NANCY, France
[email protected]
Grenoble, France
Pr Jean-François Payen
Département d'Anesthésie-Réanimation
Hôpital Michallon. BP 217
38043 Grenoble Cedex
Phone: (33) 4 76 76 55 96
Fax :(33) 4 76 76 51 83
[email protected]
Pr Jean François LeBas
Chef de service de Neuroradiologie
Hôpital Michallon. BP 217
38043 Grenoble Cedex
[email protected]
Montpellier, France
Pr Alain Bonafe
Service de Neuroradiologie
Hôpital Gui de Chauliac - 34295 MONTPELLIER
Phone: (33) 4 67 33 75 32
[email protected]
[email protected]
Docteur Edith André
Département d’Anesthésie Réanimation
DAR C - Hôpital Gui de Chauliac –
80 av augustin fliche - 34295 MONTPELLIER CX 5
Phone : (33) 4 67 33 63 57 / 74 67 - secretary : (33) 4 67 33 76 87
[email protected]
Bordeaux, France
Pr François Sztark
20
Dr Françoise Masson
Département d'Anesthésie-Réanimation
CHU Bordeaux,
1, pl. Amélie Raba-Léon
Barriére d'Ornano
Bordeaux
[email protected]
[email protected]
Pr Vincent Dousset
Département de Neuroradiologie
CHU Bordeaux,
1, pl. Amélie Raba-Léon
Barriére d'Ornano
Bordeaux
[email protected]
Liège, Belgium
Pr. Steven Laureys
Cyclotron Research Center and Department of Neurology,
University of Liège,
Sart Tilman B30, 4000 Liège, Belgium
[email protected]
Geneva, Switzerland
Dr. Yvan Gasche
Médecin adjoint du chef de service
Service des Soins Intensifs, Neuroréanimation
Hôpitaux Universitaires de genève
24 Rue Micheli-du-Crest
1211 Genève, Suisse
Phone: (41) 2 23 72 33 11 beep 6858646
Fax: (41) 2 23 82 74 70
[email protected]
21