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

STATISTICAL ANALYSIS PLAN FOR  
DEXCON-TBI trial 
 
1. INTRODUCTION 
1.1 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 protocol 
DEXCON-01-2019; Versión 1/October 2019 
approved by the IRB: November 27, 2019 
 
1.3 Trial registration 
ClinicalTrials.gov number: NCT04303065 
EUDRA number: 2019-004038-41 
 
1.4 Author(s) of 
statistical analysis 
plan 
Jon Pérez-Bárcena; PhD (1) 
Guillem Frontera Juan; PhD (2)  
1. Neuro UCI. Servicio de Medicina 
Intensiva. Hospital Universitario Son 
Espases. Instituto de Investigación de las 
Islas Baleares (IDISBA). Palma. Spain 
2. Unidad de Ensayos Clínicos. Hospital 
Universitario Son Espases. Instituto de 
Investigación de las Islas Baleares 
(IDISBA). Palma. Spain 
 
 
 
 
 

 
2. LOGIC MODEL 
Has the project’s logic model (setting out the underlying 
logic or theory of change and a set of assumptions about 
how an intervention works) changed since the trial protocol 
was completed?  
NO 
 
 
 
3. CONSTRUCTION OF KEY VARIABLES 
 
Primary of 
secondary 
outcome? 
Description of 
variable 
Detailed definition 
Any 
significant 
changes 
made since 
the trial 
protocol 
Primary 
Proportion of 
patients with good 
recovery (Glasgow 
Scale Outcome 
Extended 7 and 8) 
at 1 and 6 month 
after injury. 
 
The scale will be 
dichotomized in 
unfavorable 
outcome (GOSE 1-
6) and favorable 
outcome (GOSE 7-
8). 
The GOSE is an 
ordinal scale on which 
each increment 
represents a better 
quality of recovery. A 
GOSE score of 1 
indicates death, 2 a 
vegetative state, 3 or 4 
severe disability, 5 or 6 
moderate  
Disability, and 7 or 8 
good recovery. 
 
Since the severity of 
the initial injury will 
significantly determine 
the final outcome of the 
no 

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 
Volume of 
pericontusional 
edema before and 
after 12 days of 
treatment in both 
groups of patients. 
 
Semi-automated 
manual segmentation 
of all intracranial 
traumatic lesions 
(contusions including 
both hyperdense and 
hypondense areas, 
subdural hematoma, 
epidural hematoma, 
subarachnoid 
hemorrhage and 
intraventricular 
hemorrhage) wil be 
performed. 
The imaging data were 
pseudonymized and 
uploaded to the 
QUIBIM Precision® 
platform (version 3.0.3; 
Quibim, Valencia, 
Spain), which was 
specifically designated 
no 

for this study 
Secondary 
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 
 
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. 
presence of psychotic 
symptoms using the 
Confusion Assessment 
Method (CAM). 
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. 
 
no 
Secondary 
Number of 
episodes of 
neurological 
deterioration in 
both groups of 
patients 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 than that 
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 
no 
Secondary 
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. 
no 

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.  
 
Secondary 
Compare the 
results of the 
neuropsychological 
tests between the 
two groups of 
patients one month 
and 6 months after 
the TBI. 
-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 
no 

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. 
 
 
 
 
4. DATA CLEANING 
Describe any steps that you intend to take to prepare the data for analysis, 
including whether any observations will be excluded from the analysis and how 
you will deal with missing data. 
 
 
Handling of missing data in outcome 
measures 
missing values  will be excluded from 
the analysis  
 
Criteria to be used to exclude 
observations from the analysis 
None 
Any additional data cleaning 
None 
 
 
 
 
 
 
 

5. MAIN ANALYSIS 
 
 
Default approach 
Primary approach to be 
used 
Type of treatment effect 
to be estimated 
Modified intention-to-
treat  
Modified intention-to-
treat basis, which 
included 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 
Treatment groups to be 
compared 
Treatment group against 
control group. 
 
Dexamathasone vs 
placebo 
Type of statistical test 
The primary analysis will 
compare the baseline 
variables between both 
groups. 
 
 
 
In the secondary analysis 
we will measure the effect 
of dexamethasone and 
placebo on the patient´s 
functional status measured 
with the GOSE at one 
month and at 6 months, 
including the sliding the 
sliding dichotomy 
approach. 
 
 
 
 
Values will be expressed 
as number of patients 
and percentage or 
median and first-third 
quartile (Q1-Q3) 
 
Between group 
differences were 
calculated as the value 
of the dexamethasone 
group minus the value in 
the placebo grupo. ARR: 
Absolute Risk Reduction 
 
Unadjusted t-test (for 
continuous variables); 
Chi-squared test (for 
binary variables); 
Mann-Whitney U test to 
compare median values 
 
Subgroup analysis 
we will conduct a pre-
specified subgroup 
analyses in those 
patients with baseline 
pericontusional edema 
greater than 10 ml in the 
pre-inclusion CT scan 
As our hypothesis holds 
that dexamethasone 
could exert its beneficial 
effect by reducing the 
pericontusional edema, 
we conducted a pre-
specified subgroup 
analyses in those 

patients with baseline 
pericontusional edema 
greater than 10 ml in the 
pre-inclusion CT scan