The statistical study design is conceived in 2 steps.

Step 1. An interim safety analysis will be performed to evaluate separately in each of the two

experimental dosage groups plus placebo group (12 evaluable patients in each group  - 36 patients overall). 

According to the above rules:

- if both experimental treatments are considered not safe, the study will be stopped for safety issues

and the step 2 of the study will not be performed.

- If one experimental treatment is considered safe and the other not safe, only the safe arm will

proceed with the step 2 of the study.

- If both the experimental dosages are safe, then the more active schedule will be selected for the

step 2.

Step 2. The primary endpoint will be the neurofilament dosage after 14 days. 

The total number of evaluable patients to be analyzed will be 66 (15 patients on the control arm,

15 in the experimental arm selected during the interim analysis - plus the first 36 patients as explained above). 

Expecting a 13% of deaths of TBI patients in ICU, the number of patients to be randomized is about

78.