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

 
1. INTRODUCTION 
 
1.1 Complete project title 
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) 
 
1.2 Trial registration  
ClinicalTrials.gov number: NCT04303065 
EUDRA number: 2019-004038-41 
1.3 Protocol version 
DEXCON-01-2019; Versión 1/October 2019 
approved by the IRB: November 27, 2019 
 
 
 
2. OBJECTIVES AND RATIONALE 
2.1 Research questions 
To estimate the efficacy of dexamethasone, with respect to placebo 
in patients with TBI and brain contusions and pericontusional 
edema.  
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). 
 
2.2 Background and 
rationale 
Traumatic Brain Injury (TBI) is a global public health problem as 
there are more than 50 million cases of TBI per year worldwide. It 
constitutes one of the main causes of death and disability 
secondary to trauma and causes a great emotional and economic 
burden for the patients themselves, their families and the society. 
TBI is a complex and heterogeneous pathology, and this is one of 
the main reasons that could explain why the vast majority of clinical 
trials have failed in these patients.  Among the drugs that have 
been tested in clinical trials in patients with TBI are glucocorticoids. 

Based on the results of the MRC CRASH study, the current Clinical 
Practice Guidelines of the Brain Trauma Foundation do not 
recommend the administration of high doses of 
methylprednisolone to improve the prognosis for patients with TBI. 
However glucocorticoids, mainly dexamethasone, are still used in 
neurosurgical patients with various pathologies. For example, the 
benefit of dexamethasone in symptomatic patients with brain 
tumors and significant peritumoral edema, which is primarily 
vasogenic, has been well suggested. 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.  
TBI patients with brain contusions are a subgroup of TBI that can be 
clearly and practically defined on non-contrast head computed 
tomography (CT). They occur in approximately 35% of moderate-
severe TBI cases. Contusion expansion, constituting progression of 
both hemorrhage and cerebral edema, occurs in approximately 
50% of patients.  Usually, the hemorrhage progression occurs most 
frequently within the first 12–24 hours, and the increase of the 
pericontusional edema occurs subsequently. Both increases can 
cause a rise of the intracranial pressure (ICP), leading to subsequent 
neurological deterioration. Currently there are no available 
therapies to prevent or treat this process. 
 
Published studies have described the presence of a mixed 
component of cerebral edema (vasogenic and cytotoxic) in patients 
with TBI and cerebral contusions.  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.  
For this reason, and taking into account the above mentioned 
preliminary results, the DEXCON-TBI trial was designed to assess 
the effect of dexamethasone in the clinical outcomes of TBI 
patients with brain contusions and pericontusional edema. In this 
study we tried to address TBI heterogeneity by limiting the 
enrolment to TBI patients with brain contusion and pericontusional 
edema. Our hypothesis was that dexamethasone can reduce the 
pericontusional edema and therefore improve clinical outcomes in 
this specific subtype of TBI patients.  

 
3. ROLES AND RESPONSIBILITIES 
3.1 Roles and 
responsibilities 
Trial steering committee (TSC) 
Dr Jon Pérez Bárcena. Intensive Care Department. Son Espases 
Hospital. Palma de Mallorca. (Principal investigator) 
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. 
 
 
Statistician and Trial management:  
Dr Guiem Frontera 
Unidad de Ensayos Clínicos. Hospital Universitario Son Espases. 
Instituto de Investigación de las Islas Baleares (IDISBA). Palma. 
Spain 
 
Pharmacy Department:  
Leonor Periañez Párraga 
Phamacy Department. Son Espases Hosptial. Palma de Mallorca 
 
 
 
4. PARTICIPANTS, INTERVENTIONS AND OUTCOMES 
 
4.1 Participants 
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. 
 
4.2 Interventions 
Dexamethasone will be compared with matching placebo. 
 
Once it was verified that the patient met all the inclusion criteria 
and none of the exclusion criteria, a written informed consent will 
be obtained from the patients or from their legal representative if 
they lacked the capacity to provide consent. Then, a correlatively 
treatment kit will be assigned to the patient. 
 
Dexamethasone dosage 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).  The patients in the placebo arm will receive the 
same amount of capsules. 
 
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. 
 
4.3 Outcomes 
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).The scale will be 
dichotomized in unfavorable outcome (GOSE 1-6) and favorable 
outcome (GOSE 7-8).  
 
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. 
 
 
Secondary outcomes 
-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. 
 
5. TRIAL DESIGN 
5.1 Description 
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.  
 
 
 
5.2 Trial diagram 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 

6. SAMPLING AND RANDOM ASSIGNMENT 
6.1 Sampling plan 
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. 
 
6.2 Process for random 
allocation 
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. 
 
 
 
 
 
 
 
 
 

7. STATISTICAL ANALYSIS 
 
7.1 Intended comparisons 
- Proportion of patients with good recovery (Glasgow Scale 
Outcome Extended 7 and 8) 
 
- 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. Adverse events of special interest included 
hyperglycemia, new-onset delirium and infections 
-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 
7.2 Statistical methods 
used 
The primary analysis will compare all patients allocated to 
dexamethasone versus those allocated to placebo, on an 
‘modifiend intention-to-treat’ basis. 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 the effect of dexamethasone and 
placebo on the patient´s functional status will be compared 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).  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'. 
 
Between group differences will be calculated as the value of the 
dexamethasone group minus the value in the placebo grupo 
 
Values will be expressed as number of patients and percentage or 
median and first-third quartile (Q1-Q3) 
 
Unadjusted t-test (for continuous variables); chi-squared test (for 
binary variables); Mann-Whitney U test to compare median values 
will be used. 
 

7.3 Additional analysis 
We will conducta a pre-specified subgroup analyses in those 
patients with baseline pericontusional edema greater than 10 ml 
in the pre-inclusion CT scan 
 
 
 
 
8. SAMPLE SIZE AND STATISTICAL POWER 
8.1 Assumptions used for 
power calculations 
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%. 
 
 
8.2 Sample size required or 
minimum detectable 
effect size(s) 
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). 
 
 
 
9. DATA COLLECTION 
 
9.1 Data sources 
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. 
 
9.2 Assessment of data 
completeness 
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. 
 
9.3 Assessment of data 
quality 
All completed questionnaires will be reviewed at the coordinating 
center by a clinically trained investigator who was unaware of the 
trial-group assignments. 
 
 
 
10. ETHICS 
10.1 Ethical concerns 
Dexamethasone has a well documented safety profile. 
Nevertheless, data on adverse events, such as infectious 
complications, hyperglycemia or appearance of psychotic 
symptoms  will be collected as secondary outcomes. 
 
 
10.2 Consent or assent for 
participation in the trial 
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 inclusion 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. 
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. 
 
10.3 Confidentiality 
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. 
 
10.4 Data protection 
The data collected for the study will be identified with a code so 
that no information that could identify the patient is included, and 
only the study's research physician will be able to link the data to 
the patient and their medical history. 
 
10.5 Declaration of 
This trial is funded by the Sociedad Española de Medicina Intensiva 

interest 
y Unidades Coronarias (SEMICYUC) and the Fundación Mutua 
Madrileña. 
 
The funder of the study had no role in study design, data 
collection, data analysis, data interpretation, or writing of the 
report. 
 
 
 
 
11. TIMELINE  
 
Date 
Activity 
July 15; 2020 
Study start 
June 26; 2021 
Fundación Mutua Madrileña 1-year grant  
August 1; 2022 
Interim analysis 
June 27;2023 
Fundación Mutua Madrileña 2-year grant 
June 30; 2025 
End of the Mutua Madrileña 2-year grant 
June 30; 2025 
End of recruitment