Dexamethasone for the Treatment of Traumatic Brain Injured Patients With Brain Contusions and Pericontusional Edema: Study Protocol for a Prospective, Randomized and Double Blind Trial.
Phase: PHASE3
Conditions: Traumatic Brain Injury, Cerebral Edema, Head Injury Trauma
Sponsor: Jon Pérez Bárcena

DEXAMETHASONE FOR THE TREATMENT OF TRAUMATIC BRAIN INJURED 
PATIENTS WITH BRAIN CONTUSIONS AND PERICONTUSIONAL EDEMA: STUDY 
PROTOCOL FOR A PROSPECTIVE, RANDOMIZED AND TRIPLE BLIND TRIAL. 
(DEXCON TBI TRIAL) 
DEXCON-01-2019; Versión 1/October 2019 
approved by the IRB: November 27, 2019 
EudraCT: 2019-004038-41; Clinical Trials: NCT04303065 
 
Jon Pérez Bárcena MD; PhD (1) * (Principal investigator) 
1) Intensive Care Department. Son Espases Hospital. Palma de Mallorca 
 
 
 
 
 
 
 
 
*Corresponding author: 
Jon Pérez-Bárcena MD, PhD. 
Intensive Care Department. Son Espases University Hospital 
Carretera de Valldemossa, 79 
07120, Palma de Mallorca (Islas Baleares). Spain. 
Phone: +34 871 275 000 (ext 75974) 
Email: juan.perez@ssib.es 
 

BACKGROUND 
Traumatic brain injury (TBI) is defined as an alteration in brain function caused by an 
external force.  It is usually classified according to the neurological examination 
obtained by the Glasgow coma scale exam (GCS) in mild TBI (GCS 14-15 points), 
moderate (GCS 9-13 points) or severe (GCS less than 8 points). TBI is a global public 
health problem as there are more than 50 million cases of TBI per year wordlwide (1), 
and it is one of the main causes of death and disability secondary to trauma, causing a 
great emotional and economic burden for the patients themselves, their families and 
society in general. Data published by Eurostat from 24 European countries show that in 
2012 there were 1.5 million hospital discharges and 57,000 deaths attributable to TBI 
(2). In 2010, the costs associated with TBI in Europe were estimated at 33 billion euros 
(3). In addition, the incidence of TBI has increased in recent years due to the use of 
motor vehicles in developing countries and the increase in casual falls in an 
increasingly aging population in developed countries (1).  
 
In recent years, the prognosis of this type of patients has not varied substantially (4). 
Various explanations for this observation have been described.  One reason could be 
the increase in age in patients with TBI. Older patients are more likely to have 
complications and therefore these complications could mask an improvement in the 
management of this type of patients and therefore the prognosis (5). In addition, head 
trauma is a complex and heterogeneous pathology, and these are two of the reasons 
why the vast majority of clinical trials have not shown beneficial results of drugs so far 
(1,6), except the CRASH-3 trial with tranexamic acid (7). The most cited reasons for 
this failure in clinical trials (1,6,8) include the heterogeneity of this pathology;  the 
absence of analytically valid biomarkers or surrogate variables, and the lack of 
variables or study methods sensitive enough to detect differences between groups. 
 
Among the drugs that have been tested in clinical trials in patients with TBI are 
corticosteroids. Based on the results of the MRC CRASH study (9), the current Clinical 
Practice Guidelines (10) do not recommend the administration of high doses of 
methylprednisolone to improve the prognosis for patients with TBI. However, due to the 
experience of dexamethasone in patients with brain tumors, this glucocorticoid is still 
used in neurosurgical patients with various pathologies and its role is currently being 
reassessed in patients with TBI and chronic subdural hematomas (11,12).  

In daily clinical practice, patients with TBI and cerebral contusions developing and area 
of pericontusional edema are among the patients who are occasionally given 
dexamethasone on the belief that this edema is similar to that of tumors. Clinically, the 
beneficial effect of dexamethasone in patients with tumors and peritumoral edema, 
which is primarily vasogenic, has been well demonstrated (13).  
 
Cerebral edema is classified as cytotoxic and vasogenic. Cytotoxic edema is primarily 
intracellular and appears after ischemic insults. In vasogenic edema, however, water 
has an extracellular location and appears when there is a disruption or an abnormal 
increase in the permeability of the blood brain barrier (14). Published studies have 
described the presence of a mixed component (vasogenic and cytotoxic) in patients 
with TBI and cerebral contusions (15,16). Experimental studies have shown that the 
alteration of the blood brain barrier is biphasic. There is a rapid initial opening phase 
after the trauma that occurs in the first hours. Subsequently, a second opening phase 
of the blood brain barrier occurs, which usually begins between 3-7 days after the 
trauma (17). At the clinical level it has been proven that can take days or weeks for the 
blood brain barrier to return back to normal (17,18). For this reason it is possible that 
there is a therapeutic window for corticosteroids in this type of patients. However, it is 
well known that corticosteroids have a beneficial effect on vasogenic edema (as in 
patients with tumors) but none on cytotoxic edema. 
 
Using diffusion tensor magnetic resonance imaging (DT-MRI), our group has shown 
that the radiological characteristics of the vasogenic edema in patients with brain 
tumors and cerebral contusions are similar. Specifically, the apparent diffusion 
coefficient (ADC) and fractional anisotropy (FA) were similar in both groups of patients 
(19). We have also observed, using DT-MRI, in a group of 30 patients with TBI, 
cerebral contusions and pericontusional edema, that the use of dexamethasone at low 
doses was associated with a reduction in the volume of cerebral edema and 
improvement in radiological parameters (ADC and FA). (author´s unpublished data). 
 
For this reason, and taking into account the preliminary results mentioned in the 
previous paragraph, it is intended to conduct a clinical trial to assess the effect of 
dexamethasone on the prognosis of TBI patients with brain contusions and 
pericontusional edema.  The idea of guiding the treatment of patients with TBI and 

cerebral contusions depending on the type of edema can be very useful and a novel 
way of designing this clinical trial.  
 
To conclude and as described in the third paragraph, the current Clinical Practice 
Guidelines (10) do not recommend the administration of high doses of 
methylprednisolone to improve the prognosis for patients with TBI. In our opinion this 
does not mean that the effect of low doses of dexamethasone (maximum dose of 16 
mgr per day) should not be studied in a short and descending course to a selected 
group of patients such as patients with cerebral contusions and pericontusional edema. 
This dose is the usual one in neurooncology and there is an extensive experience in its 
use. In addition, two clinical trials with dexamethasone at these doses are already 
being conducted in patients with TBI but with chronic subdural hematomas (11,12). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

OBJECTIVE 
To estimate the efficacy of dexamethasone, with respect to placebo in patients with TBI 
and brain contusions.  
 
METHODS, DESIGN, DISCUSSION 
Overview 
The DEXCON TBI trial is a multicenter, pragmatic, randomized, triple-blind, placebo 
controlled trial to quantify the effects of the administration of dexamethasone on the 
outcome of TBI in TBI patients with brain contusions and pericontusional edema.  
Pragmatic design and the uncertainty principle 
The design will allow us to find out how effective the treatment actually is in routine 
everyday practice. Ethically, this randomized controlled trial can only be undertaken if 
there is collective scientific uncertainty about which of the interventions being 
compared is more likely to benefit patients. However, for an individual clinician to be 
able to recommend enrolment of a patient into a trial, they must be substantially 
uncertain about the appropriateness of the trial treatment in that particular patient. The 
eligibility criteria for the DEXCON trial are based on this uncertainty principle. A patient 
can be enrolled only if the responsable clinician is substantially uncertain as to which of 
the trial treatments would be most appropriate for that particular patient. Using the 
uncertainty principle should allow the process of this trial to be closer to what is 
customary in normal medical practice. 
Eligible patients 
Adults with TBI who fulfill the following inclusión criteria are eligible: 
-Patients who have suffered a head injury and have one or more cerebral contusions 
with visible pericontusional edema in the CT scan.  
-Patients with brain contusions in whom non-sugical treatment has been selected 
initially. 
-Age 18 or over and under 85 
-Signing of informed consent by the patient or by his legal representative. 

The fundamental eligibility criterion is the responsible clinician’s ‘uncertainty’ as to 
whether or not to use dexamethasone in a particular patient with TBI. This pragmatic 
approach will allow us to see whether the intervention improves patient outcomes 
under real-life conditions. 
The exclusion criteria are the following: 
-Patients with TBI and brain contusions who have required surgery to evacuate the 
cerebral contusion before randomization. 
-Patients with TBI who have required a craniotomy before randomization for any other 
reason: evacuation of subdural, epidural hematoma or depressed skull fracture. 
-Patients with an extracranial Injury Severity Score greater than 18 points. 
-Patients in whom the use of corticosteroids is contraindicated. 
-Patients who take oral corticosteroids chronically. 
-Patients included in another clinical trial. 
-Known intolerance or hypersensitivity to dexamethasone. 
-Patients with allergy or intolerance to the following excipients contained in 
dexamethasone / placebo capsules: lactose, corn starch or microcrystalline cellulose. 
-Patients with a history of psychotic disorders. 
-Patients with inability to take medication orally due to swallowing problems in which it 
is not indicated to place a nasogastric tube. 
-Pregnant or breastfeeding patients. 
-Patients in a GCS 3 points situation with bilateral dilated pupils. 
-Patients with associated spinal cord injuries. 
-Patient with any systemic condition that contraindicates the use of corticosteroids. 
Randomization 
To ensure a balanced sample size across groups over time, the statistician of the study 
will apply the block randomisation method with a block size of 2 (two possible 
sequences: AB and BA) and will be generated with the statistical package R, version 
3.5.3, a list for each hospital. A limited number of treatments will be available in each 

hospital, sent from the Pharmacy Department of Son Espases Hospital, which will be 
numbered, and will be assigned in a correlative manner. 
Patients, clinical staff, evaluators of the results as well as the statistical team will be 
blinded to the assignment of medications.  
Only the pharmacist, who masks the capsules and labels the containers, will know the 
assignement of the codes, and will keep them blind until the last phase of the study, 
after the main statistical analysis, or when unmasking is required. 
Once it is verified that the patient meets all the inclusion criteria and none of the 
exclusion criteria, and after signing the informed consent by the patient himself or by 
the closest relative, the doctor responsible for the patient will correlatively assign the 
number to the patient. 
Settings 
Initially, the study will be carried out in Son Espases Hospital (Palma de Mallorca) and 
12 de Octubre Hospital (Madrid).  During the first year, all possible patients will be tried 
to be recruited. A minimum of 60 patients are expected between the two hospitals.  
If after the first year interim analysis the Trial Steering Committee (TSC) decides to 
continue the trial, recruitment will begin in the hospitals included in the Spanish 
National Registry of Traumatic patients in the ICU (RETRAUCI Network) which 
includes 56 public hospitals. 
 
Outcome measures 
After a patient has been randomized, the outcome will be collected even if the trial 
treatment is interrupted or is not actually given 
 
Primary outcome 
The primary outcome is the functional status (outcome) of TBI patients one and six 
months after the trauma according to the Glasgow Scale Outcome Extended (GOSE). 
 
Secondary outcomes (Supplemental data) 
-Number of episodes of neurological deterioration in both groups of patients during the 
12 days of treatment. 

-Symptoms associated with TBI in both groups of patients during the 12 days of 
treatment. 
-Volume of pericontusional edema before and after 12 days of treatment in both groups 
of patients. 
-Presence of adverse events between the two groups during the 12 days of treatment. 
-Neuropsychological tests between the two groups of patients one month and 6 months 
after the TBI. 
 
Estimated event rate 
In our previous studies we have described that among TBI patients with brain 
contusions not treated with dexamethasone, the proportion of patients with good 
recovery (GOSE 7 and 8) was 50%. 
 
Sample size and treatment effect size that should be detectable 
Since the data available in this type of patients with this treatment is scarce and 
inconclusive, we will perform a randomized, triple-blind, placebo controlled trial with an 
interim futility analysis (interim analysis). The primary endpoint for the DEXCON TBI 
trial is the good recovery (GOSE 7-8) one month after the TBI. 
A study with 600 patients would have about 80% power (two sided alpha=5%) to detect 
a 12% absolute increased (from 50% to 62%) in good recovery (GOSE 7-8). It includes 
an inflation of 10% due to non-adherence (withdrawal of consent, loss to follow-up, 
cross-over or change of treatment). 
Recruitment of collaborating investigators 
The trial will recruit hospitals from Spain. Suitable collaborating hospitals and 
investigators will be assessed in terms of the trauma service that they provide and their 
ability to conduct the trial.  
Before the trial can begin at any site, the local Principal Investigator must agree to 
adhere to Good Clinical Practice Guidelines and all relevant national regulations. In 
addition, all relevant regulatory and ethics approvals should be in place before the trial 
starts at a site. 

Ethical considerations, information giving and written informed consent 
The GCS score is a method of assessing the level of consciousness in TBI patients. 
Patients with a GCS score of 15 are generally considered fully conscious, but those 
with a GCS score of 14 or less may not be fully conscious and would not be mentally 
capable of giving informed consent to participation in a clinical trial. Besides, a brain 
contusion is a clinical sign indicating significant brain injury, and patients with this 
diagnosis would not be physically or mentally capable of givin informed consent to 
participation in a clinical trial. 
Therefore, given that patients are eligible for inclusión in the DEXCON TBI trial if they 
have a TBI and have a brain contusion on a CT scan, in most cases they will, by 
default, be physically or mentally incapable of giving consent.  
Prior information giving to the patient´s relatives 
If relatives are present, they will be provided with brief information about the trial. 
Specifically, the responsible doctor will explain to the relatives that the patient will 
receive the usual treatments for traumatic brain injury but that, in addition to these, the 
patient has been enrolled in a research study that aims to improve the treatment of 
patients with this condition. 
It will be explained that the study is being done to see whether using a drug called 
dexamethasone will help patients with head injury by reducing the amount of edema 
and inflammation into the brain, therefore preventing further brain damage. The relative 
will be informed that the patient will be given a treatment over 12 days of either 
dexamethasone or a dummy medicine (a capsule which does not contain 
dexamethasone). The doctor will explain that dexamethasone has been shown to 
improve outcome in patients with other types of brain injuries, such as tumors, and that, 
whilst we hope that it will also improve recovery after head injury, at present we cannot 
be sure about this. If requested, a brief information sheet will be provided. If relatives 
object to the inclusion of the patient in the trial, their views will be respected. If no 
relatives are present, the patient can not be included in the study. 
 
 
 
 

Treatment 
Dexamethasone will be compared with matching placebo. 
Dose selection 
Dexamethasone doses are those commonly used in neurooncology and there is an 
extensive experience in its use. It will be a short and descending course: 4mg/6 hours 
(2 days); 4 mg/8 hours (2 days); 2 mg/6 hours (2 days); 2 mg/8 hours (2 days); 1 mg/8 
hours (2 days); 1 mg/12 hours (2 days). 
Drug manufacture, blinding and supply of trial treament 
Dexamethasone (Fortecortin®) will be acquired from ERN, SA. Laboratories 
(Barcelona, Spain). The Son Espases Pharmacy Department will be in charge of 
developing and conditioning the 4mg, 2mg and 1mg dexamethasone / placebo 
capsules needed for 12 days of treatment, keeping the researchers blind.  
The preparation and conditioning of the capsules will be carried out following the 
standardized work procedures of the pharmaceutical laboratory and its quality controls, 
previously authorized by the Agencia Española del Medicamento (AEMPS). 
The Son Espases Pharmacy Department will be responsible for identifying the 
containers and sending them by courier to the participating hospitals. A record of the 
dispensing of test samples will be kept and will be sent in acknowledgment of receipt 
for control. 
Patients, clinical staff, evaluators of the results as well as the statistical team that will 
perform the analysis will not know the assigned treatment. A randomization list will be 
created for each hospital. The randomization sequence will only be known by the 
Pharmacy Department of Son Espases Hospital. 
Administration of trial treatment 
Each patient will receive 3 containers with the correspondingly identified doses, and an 
information sheet explaining dose and frequency for proper oral administration. 
Other treatments for traumatic brain injury 
There is a wide spectrum of treatments for TBI. As the trial will be conducted in Spain, 
each participating site should follow its own clinical guidelines for the treatment of TBI 
patients. There is no need to withhold any clinically indicated treatment in this trial. 

Dexamethasone or placebo would be provided as an additional treatment to the usual 
management of TBI. 
Safety and Adverse events 
Dexamethasone has a well documented safety profile. Nevertheless, data on adverse 
events, such as infectious complications, hyperglycemia, gastro intestinal bleeding or 
appearance of psychotic symptoms  will be collected as secondary outcomes and will 
be presented to the independent Data Monitoring Committee (DMC) for blinded review. 
Definitions 
Adverse events (AE): Any undersirable and unintended medical occurrence 
affecting a trial participant during the course of a clinical trial. 
Serious adverse events (SAE): A serious adverse event (experience) is any 
undersirable medical occurrence that results in death or is life-threatening or requires 
inpatient hospitalization or prolongation of existing hospitalization, or results in 
persistent or significant disability/incapacity. 
 
Reporting of adverse events for this trial 
Death, life-threatening complications, and prolonged hospital stay which is attributable 
to the adverse event are pre-specified outcomes to be reported in this trial. This clinical 
trial is being conducted in an emergency condition using a drug in common use. It is 
important to consider the natural history of the critical medical event affecting each 
patient enrolled, the expected complications of this event, and the relevance of the 
complications to dexamethasone.  
Adverse events to be reported using an adverse event reporting form will be limited to 
those trial outcomes that might occur and be reasonably attributable to the trial drug. 
Events that are part of the natural history of the primary event of TBI or expected 
complications of TBI should not be reported as adverse events.  
If an SAE occurs, a written report must be submitted within 24 h. The Trial Steering 
Committe (TSC) will coordinate the reporting of all SAEs to all relevant Regulatory 
Agencies, Ethics Committees and local investigators as per local legal requirements. 
 

Unblinding 
In general there should be no need to unblind the allocated treatment. Unblinding 
should be done only in those rare cases when the clinician believes that clinical 
management depends importantly upon knowledge of whether the patient received 
dexamethasone or placebo. In those few cases when urgent unblinding is considered 
necessary, a 24-h telephone service will be available. The caller will be told whether 
the patient received dexamethasone or placebo.  
Data collection and management 
This trial will be coordinated from Son Espases Hospital. Data will be collected at each 
site by local investigators and sent to the TSC. These data will be collected from the 
patient’s routine medical records and no special tests will be required.  
All data on adverse events, including those routinely collected as outcomes, will be 
collected and reported as recquired by the relevant authorities. 
Data will be collected by the investigator on the paper Case Report Forms (CRFs) and 
transmitted to the TSC through the Research Electronic Data Capture (REDCap). 
REDCap is a secure web application for building and managing online surveys and 
databases. Original paper CRFs will remain at each trial site. The data will be used in 
accordance with local law and ethics committee approval. 
Monitoring  
The intervention with dexamethasone has marketing authorization in Spain and has 
been in clinical use for decades. Its safety profile is well established and no significant 
serious adverse events associated with its use have been identified. The trial will 
routinely collect data on adverse events which may theoretically be associated with this 
product and the condition under investigation, and these will be reviewed by the 
independent DMC. 
The trial procedures are based on routine clinical procedures and include (1) the oral 
administration of the trial drug using routine clinical use; (2) collecting routine clinical 
information from the medical records; and (3) informed consent. There are no complex 
procedures or interventions for the participants or investigators in this trial. Clinical 
management for underlying conditions will remain as per each hospital’s standard 
protocol. 

Investigators/institutions 
are 
required 
to 
provide 
direct 
access 
to 
source 
data/documents for trial related monitoring, audits, ethics committee review and 
regulatory inspection. All trial-related and source documents must be kept for at least 5 
years after the end of the trial. 
End of trial for participants 
For the recruited patients the trial ends at death or at 6-month follow-up, whichever 
occurs first. If during the treatment phase a patient develops an adverse event, the trial 
drug should be stopped, the patient treated in line with local procedures, and then 
followed up.  
The trial may be terminated early by the Trial Steering Committee (TSC). The 
independent DMC may give advice/recommendation for the early termination of the 
trial but the TSC is responsible for the final decision. 
Analysis 
The primary analysis will compare all patients allocated to dexamethasone versus 
those allocated to placebo, on an ‘modified intention-to-treat’ basis. Modified intention-
to-treat basis, which will include all patients who were randomly assigned, except those 
who withdrew consent, those who were lost the follow up or had protocol violations. 
Protocol violations corresponded to those patients who did not complete the 12-day 
treatment duration. A descriptive analysis of the baseline variables will be made for 
each treatment group, followed by a comparison between both groups.  
In the secondary analysis a logistic regression model will be built to estimate the effect 
of dexamethasone and placebo on the patient´s functional status measured with the 
GOSE at one month and at 6 months. The scale will be dichotomized in unfavorable 
outcome (GOSE 1-6) and favorable outcome (GOSE 7-8). In this analysis the primary 
outcome will be adjusted by age, pupil reactivity, blood pressure and GCS. To choose 
a model, the adequacy and goodness of fit will be measured.   
Since the severity of the initial injury will significantly determine the final outcome of the 
patient, regardless of any treatment, the results of this study will be analyzed using the 
'sliding dichotomy'. According to this analysis, patients with a less severe initial injury 
should have a better recovery than those with a severe initial injury. For example, a 
moderate disability in a patient for whom no more than death or severe disability could 
be expected is considered a good outcome, and vice versa, consider a moderate 
disability in a patient with excellent initial prognosis as poor outcome.  Patients with a 

severe initial injury (GCS score of 4 to 5 or, or with a GCS motor score of 2 to 3) will be 
considered to have a favorable outcome if the 6-month GOS-E score is 3 or higher. 
Patients with a moderate-to-severe initial injury (GCS score of 6 to 8 or, GCS motor 
score of 4 to 5) will be considered to have a favorable outcome if the 6-month GOS-E 
score is 5 or higher, and those with a less initial injury (GCS score of 9 to 12, GCS 
motor score of 6) will be considered to have a favorable outcome if the 6-month GOS-E 
score is 7 or higher. 
The purpose of the sliding dichotomy approach is to increase the sensitivity (to lower 
the false negative rate) of the analysis. All these variables will also be analyzed in a 
pre-specified subgroup analysis comparing patients with a pericontusional edema 
volume of more than 10 mL in the pre-inclusion computed tomography (CT) scan in the 
study with those who have less than 10 mL of edema volume in the same CT study. 
 
Interim analysis 
Since the data available in this type of patients receiving this treatment are scarce and 
inconclusive as to the primary outcome variable, we will perform an interim analysis. A 
statistician (Dr G Frontera) will blindly perform an interim analysis calculating the 
conditional power, an approach that quantifies the probability of obtaining a significant 
result at the end of the study given the data available after one year enrolling patients.  
Since the probablilty chosen for futility in this trial is very small (< 0,15), it can be 
concluded that it would be useless to continue the trial.  
This interim analysis will be 
performed at the end of the first year since the inception of the trial, when it is 
estimated that about 100 patients will have been recruited. At the same time, a safety 
analysis will be also perfomed, focused on the adverse effects collected during the first 
year.  
The results will be assessed and discussed by an independent Data Monitoring 
Committee, formed by one statistician and two experts in TBI, who will inform and 
make recommendations to the Trial Steering Committee, which will finally make the 
decisions. 
Follow-up 
No extra tests are required for the trial but a case report form should be completed at 
the end of the 12- day treatment, or at death or hospital discharge if either happens 
sooner. The GOSE and the neuropsychological evaluations will be performed one 
month and 6 months after the TBI. Both evaluations will be performed by clinical 

neuropsychologists, and the protocol used will always follow the same process. The 
neuropsycological tests that will be performed are described in the Supplemental data 
 
Sponsorship and trial management 
This research project has no sponsor.The trial will be coordinated by the Trial Steering 
Committee (TSC). 
Indemnity 
This project has been listed as a ``low intensity clinical trial´´ by the Agencia Española 
del Medicamento (AEMPS). In this scenario, the damages on the patient that could 
result from taking part in this trial do not need to be covered by an specific insurance 
contract if they are covered by the individual or collective professional civil liability 
insurance or equivalent financial guarantee of the health trust where the clinical trial is 
carried out.  
Protocol development 
The Protocol Committee consists of the following investigators who are responsible for 
the development of, and agreeing to, the final protocol. Subsequent changes to the 
final protocol will require the agreement of the TSC. 
Clinical experts: Dr Jon Pérez Bárcena,  Dra Ana María Castaño León, Dr Alfonso 
Lagares Gómez-Abascal, Dr Jesús Barea Mendoza, Dr Javier Ibañez Domínguez. 
Statistician and Trial management: Dr Guiem Frontera 
Independent Data Monitoring Committee (DMC) 
Dr Pedro Delgado MD. Servicio de Neurocirugía. Hospital Universitario de Burgos. 
Spain. 
Dr Marcelino Sánchez Casado MD, PhD. Servicio de Medicina Intensiva. Hospital 
Virgen de la Salud. Toledo.  Spain 
Dr Carlos Campillo Artero MD; PhD. Servei de Salut de les Illes Balears, Palma de 
Mallorca, Spain, CRES/BSM Universitat Pompeu Fabra, Barcelona Spain. 
To provide protection for study participants, an independent DMC has been appointed 
for this trial to oversee the safety monitoring. The DMC will review, after the first year, 
accumulating data from the ongoing trial and advise the TSC regarding the continuing 

safety of current participants and those yet to be recruited, as well as reviewing the 
validity and scientific merit of the trial. The statistician (Dr G Frontera) will provide (in a 
blind manner) the analysis service required by the DMC.  
Standard operating procedures 
The DMC has the responsibility for making recommendations to the TSC, while 
randomization is in progress, to unblind the results. The DMC they will do this if, and 
only if, the following two conditions are satisfied: (1) the results provide proof beyond 
reasonable doubt that treatment is on balance either definitely harmful or definitely 
favourable for all, or for a particular category of participants in terms of the major 
outcome; and (2) the results, if revealed, would be expected to substantially change the 
prescribing patterns of clinicians who are already familiar with any other trial results 
that exist. Exact criteria for “proof beyond reasonable doubt” are not specified by a 
purely mathematical stopping rule, but they are strongly influenced by such rules.  
Trial steering committee (TSC) 
Dr Jon Pérez Bárcena. Intensive Care Department. Son Espases Hospital. Palma de 
Mallorca. 
Dra Ana María Castaño León. Neurosurgery Department. 12 de Octubre Hospital. 
Madrid. 
Dr Alfonso Lagares Gómez-Abascal. Neurosurgery Department. 12 de Octubre 
Hospital. Madrid. 
Dr Jesús Barea Mendoza. Intensive Care Department. 12 de Octubre Hospital. Madrid. 
Dr Javier Ibánez Domínguez. Neurosurgery Department. Son Espases Hospital. Palma 
de Mallorca. 
Dr Guillem Frontera. Research Unit. Son Espases Hospital. Palma de Mallorca. 
The role of the TSC is to provide overall supervisión of the trial. In particular, the TSC 
will concentrate on the progress of the trial, adherence to the protocol, patient safety 
and consideration of new information. The TSC will take responsibility for: a) major 
decisions such as a need to change the protocol for any reason;  b) monitoring and 
supervising the progress of the trial;  c) reviewing relevant information from other 
sources; d) considering recommendations from the DMC. 

When outcome data are available for the participants included during the first year, the 
TSC will review the rate of recruitment into the trial and the overall event rates. The 
TSC will consider the extent to which the rate of recruitment and the event rates 
correspond to those anticipated before the trial and will take whatever action is needed 
in light of this information. 
Collaborators´responsibilities 
If after the first year interim analysis the TSC recommends to continue the trial, 
recruitment will begin in the hospitals included in the Spanish National Registry of 
Traumatic patients in the ICU (RETRAUCI Network). This network involves 56 public 
hospitals that are already actively collaborating. The coordinating center for the 
DEXCON Trial will be Son Espases Hospital (Palma de Mallorca, Spain). 
Coordination within each participating hospital will be through a local Principal 
Investigator whose responsibility will be detailed in an agreement in advance of starting 
the trial and will include: ensure all necessary approvals are in place prior to starting 
the trial; delegate trial-related responsibilities only to suitably trained and qualified 
personnel; train relevant medical and nursing staff who see TBI patients and ensure 
that they remain aware of the state of the current knowledge, the trial and its 
procedures; agree to comply with the final trial protocol and any relevant amendments; 
ensure that all patients with TBI are considered promptly for the trial; ensure consent is 
obtained in line with local approved procedures; ensure that the patient entry and 
outcome data are completed and transmitted to the TSC in a timely manner; ensure the 
Investigator’s Study File is up to date and complete; be accountable for trial treatments 
at their site; ensure the trial is conducted in accordance with  Good Clinical Practice 
Guidleines and fulfils all national and local regulatory requirements; allow access to 
source data for monitoring, audit and inspection; be responsible for archiving all original 
trial documents, including the data forms, for 5 years after the end of the trial.  
Contacting the Trial Coordinating centre in an emergency 
For urgent enquiries, adverse event reporting and unblinding queries, investigators can 
contact the 24-h telephone service provided by the TSC. A central telephone number is 
given in the Investigator’s Study File. 
Publication and dissemination of results 
All efforts will be made to ensure that the trial protocol and results arising from the 
DEXCON TBI trial are published in an established peer-reviewed journal. At least one 

publication of the main trial results will be made. The success of the trial will be 
dependent entirely upon the collaboration of the nurses and doctors in the participating 
hospitals and those who hold key responsibility for the trial. Hence, the credit for the 
study will be assigned to the key collaborator(s) from each participating site, as it is 
crucial that those taking credit for the work have actually carried it out. The results of 
the trial will be reported first to trial collaborators. 
Financial support 
The Sociedad Española de Medicina Intensiva Y Unidades Coronarias (SEMICYUC) is 
funding the run-in costs for this trial and up to 100 patients´recruitment. Full funding is 
being sought from public and private funding organizations for the main trial. Funding 
for this trial covers dexamethasone acquisition, pharmacy expenses and central 
organizational costs only. The design and management of the study are entirely 
independent of the manufacturers of dexamethasone or the funders. Review by each 
Ethics Committee and the Agencia Española del Medicamento (AEMPS)  would create 
a substantial financial burden which could limit the conduct of the trial. We request that 
payment for review of the protocol by each Committee be waived or set at a 
reasonable rate to reflect the actual cost of reviewing the trial protocol. 
 
Trial status 
Ethics approval obtained from Comité de Ética de la Investigación de las Islas Baleares 
(CEI-IB) and from Comité de Ética de la investigación del Hospital 12 de Octubre have 
been obtained. The trial has also been approved by the AEMPS, which is a public 
agency depending on the Health Ministry of the Spanish government. 
Patient recruitment is planned to take place during the first year in Hospital Son 
Espases (Palma de Mallorca, Spain) and Hospital 12 de Octubre (Madrid, Spain), and 
is active starting August 2020.  
 
 
 
 
 

 
 
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FIGURE 1. TRIAL OVERVIEW 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ELIGIBILITY CRITERIA: 
Patients who have suffered a head injury and have one or more cerebral contusions with 
visible pericontusional edema in the CT scan.  
Age 18 or over and under 85 
The fundamental eligibility criterion is the responsible clinician’s ‘uncertainty’ as to whether 
or not to use dexamethasone in a particular patient with TBI.  
Signing of INFORMED CONSENT by the patient or by his legal representative. 
RANDOMISE: dexamethasone or placebo 
Give dexamethasone or placebo during 12 days 
Complete outcome form at the end of the 12-days treatment.  
Report adverse events during the treatment period. 
Complete Extended Glasgow Outcome Scale and Neuropsycologial test 1 month after the TBI 
Complete Extended Glasgow Outcome Scale and Neuropsycologial test 6 months after the TBI 

 
 
FIGURE 2. MEASURES OF OUTCOME DURING THE TRIAL 
 
 
 
 
 
 
 
 
 
 
 

 
 
SUPPLEMENTAL DATA 1. 
Primary Outcome measurement 
The primary outcome is the Glasgow Scale Outcome Extended (GOSE) performed one 
month and 6 months after trauma. This scale will be dichotomized in favorable outcome 
(GOSE 7-8 points) and unfovable recovery (GOSE≤6 points) 
Secondary Outcome measurements 
-Compare the number of episodes of neurological deterioration in both groups of 
patients during the 12 days of treatment. 
The number of episodes of neurological impairment will be detected by the Glasgow 
coma scale and the abbreviated NIHSS scale, during the 12 days of treatment.  
An episode of neurological impairment is defined as a worsening of at least 2 points on 
the Glasgow coma scale or the NIHSS scale, which lasts at least 2 hours, and which 
cannot be fully attributed to other causes other thanthat cerebral edema. In order to 
rule out other causes of neurological deterioration, complementary tests will be 
performed according to the protocol of action of each hospital. Among these tests are 
an arterial blood gas analysis, blood test with blood count and biochemistry, 
electroencephalogram and a cranial CT scan.  
Baseline scores to compare subsequent neurological examinations will be performed 
30 minutes before starting the study medication. Subsequently, the reference scores 
will depend on the patient's clinical evolution. After sustained episodes of improvement 
or worsening in the patient's clinical situation, the baseline scores will be recalculated 
to reflect the best score of the Glasgow coma scale and the NIHSS before a possible 
episode of neurological impairment. In those patients in whom it is not possible to 
perform neurological examinations, the reason will be collected in the Investigator’s 
Study File.  
The neurological exams will be performed 3 times per day during the 12 days of 
treatment. 
-Compare the symptoms associated with TBI in both groups of patients during the 12 
days of treatment. 

The symptoms associated with TBI will be studied daily through the Rivermead Post 
Concussion Symptom (RPQ) scale. The RPQ is a questionnaire that measures the 
severity of symptoms associated with TBI. The questionnaire contains 16 symptoms 
and the patient is asked to quantify these symptoms during the past 24 hours.  
In each case, the symptoms are compared with the severity of these symptoms before 
the trauma. The symptoms range from 0 to 4 points: 0: it has not presented such a 
symptom; 1: it has not been a bigger problem than before the TBI; 2: slight problem; 3: 
moderate problem; 4: serious problem. 
The RPQ scale will be performed once daily during the 12 days of treatment. 
-Compare the volume of pericontusional edema before and after 12 days of treatment 
in both groups of patients. 
In each center, researchers will record the volume of the lesions including the 
hemorrhagic portion and the pericontusional edema using the ABC / 2 methodology. In 
the case of multiple contusions, each of them will be measured separately up to a 
number of 3, starting with the largest.  
The image will be analyzed using a standard window for all cases (window level 60 and 
width of 100 UH), thus ensuring a similar gray scale in the different centers. A 
measurement of the largest diameter (A) will be made in each contusion, followed by 
the largest perpendicular diameter to A (B) and the number of cuts in which the 
contusion (hyperintense area and perilesional hypodense area) can be identified (C). 
The total volume of the bruises will be equal to the sum of the individual volumes of 
each one, whose volume results from multiplying the three diameters and dividing them 
by two. Once this process has been carried out, a measurement will only be made of 
the hyperdense portion of the contusions to establish the volume of the edema: 
Edema volume = total volume-volume hyperdensity. 
This procedure will be performed again centrally in the 12 de Octubre hospital, Madrid.  
Previously, the patient's data will be anonymized and the images will be sent through a 
web platform with a secure server for review. In a central way, the total volume of the 
contusion will be established as well as the volume of the edema by means of a semi-
automatic method using the Analyze  software (vesion 10.0; Analyze Direct, Stilwell, 
Kansas, USA) of which a license is available. The method consists of a semi-automatic 
analysis in which in each axial section a central voxel is selected and thanks to the 
density selection, voxels with similar density characteristics are selected.  

The performance of measurements in each hospital and subsequent centralization of 
the images will allow to establish the interobserver and intermethod reproducibility of 
the measurement of the edema associated with the contusions, in addition to 
estimating in two ways the difference of measurements at two time points throughout 
the study and after an intervention. 
-Compare the presence of adverse events between the two groups during the 12 days 
of treatment. 
Those adverse effects that have special interest and serious adverse effects will be 
collected. Side effects of special interest are: 
-Metabolic: 
Hyperglycemia 
will 
be 
especially 
monitored. 
The  
the maximum value of capillary glycemia will be recorded daily. The amount of daily 
insulin that the patient needs to control de glucose level will also be collected. 
-Psychiatric: presence of psychotic symptoms using the Confusion Assessment 
Method (CAM). 
-Digestive: Episodes of gastro intestinal hemorrhage; Episodes of epigastric pain, 
vomiting or reflux symptoms. 
-Infectious: Presence of new infectious episodes. Infectious episode will be confirmed 
in accordance with the Centers for Disease Control (CDC) criteria and mainly based on 
microbiological criteria. 
- Compare the results of the neuropsychological tests between the two groups of 
patients one month and 6 months after the TBI. 
Two neuropsychological evaluations will be performed: 1 month and 6 months after the 
TBI. Both evaluations will be performed by clinical neuropsychologists, and the protocol 
to be used will always follow the same procedure and tests.  The tests that integrate 
this protocol are described below: 
-The MOCA (Montreal Cognitive Assessment): originally designed as a rapid screening 
instrument for mild cognitive dysfunction. It assesses different cognitive domains: 
attention 
and 
concentration, 
executive 
functions, 
memory, 
language, 
visuoconstructional skills, conceptual thinking, calculations, and orientation. 
- Rey Auditory Verbal Learning Test (RAVLT) is one of the most widely used word 
learning tests in clinical research and practice. Five presentations of a 15-word list are 

given, each followed by attempted recall. This is followed by a second 15-word list (list 
B), followed by recall of list A, and delayed recall and recognition are also tested. 
- Coding (WAIS-IV Battery subtest): essentially aims to assess processing speed, 
associative memory, graphomotor speed. 
- Computerized Continuous Continued Test (CPT) The CSAT-II RESEARCH  
VERSION: this version is used to evaluate sustained attention, discrimination, types of 
errors made, motor response style and response speed during the task.  
- Stroop test: This is a psychological test linked especially to neuropsychology that 
measures measuring the level of interference generated by automatisms in the 
performance of a task.  
- Digit Span (WAIS-IV Battery subtest): essentially measures auditory working memory 
and your ability to record, maintain and manipulate auditory information consciously. 
- Test Tower of London-Drexel University version test (TOLDX): measures executive 
planning ability in subjects with frontal lobe injury. Traditionally used as a planning and 
problem-solving measure. 
- Quality of Life after brain injury (QOLIBRI) Spanish version:  to measure quality of life 
after TBI. Through these scales and questionnaires, what is intended is to obtain 
information obtained, preferably, from the patient himself and simultaneously from a 
family member or friend (proxy) in order to corroborate the information provided by the 
patient himself.