Table 2 Eligibility criteria

– Age: 18–70 years (inclusive)

– Clinical frailty index  < 5 [60]

– Evidence of TBI confirmed by abnormalities consistent with trauma on CT scan upon admission (Marshall’s CT Classification > 1)

– Study drug (MSCs/placebo) administration start within 48 h from TBI

– GCS ≤ 8 at recruitment and at least one pupil reactive to light

– ICP monitoring, already inserted or planned for clinical indications

– Weight < 100 kg and > 40 kg

– Motor GCS > 5 at recruitment

– High likelihood (> 85%) of death in the first 48 h calculated by IMPACT calculator [61] on early admission data

– Bilateral unreactive mydriasis

– Opening ICP > 40 mmHg

– Known history of prior brain injury, psychiatric disorder, neurological impairment and/or deficit

– Brain penetrating injury

– Spinal cord injury

– Epilepsy requiring ongoing anti-convulsant therapy

– Severe organ failure (including PaO₂/FiO₂ < 200 and shock)

– Recent serious infectious process requiring ICU admission

– Cancer (ongoing)

– Immunosuppression

– Human immunodeficiency virus

– Positive urine pregnancy test or breastfeeding

– Known risk/history of coagulopathy and thromboembolism

– Pre-existing and severe:

  ▪ Lung disease (such as asthma, chronic obstructive pulmonary disease)

  ▪ Heart dysfunction (as heart failure and reduced cardiac output)

  ▪ Liver insufficiency (as cirrhosis)

  ▪ Kidney insufficiency

  ▪ and other organ severe abnormalities

– Known hypersensitivity to excipients used in the formulation (dimethyl sulfoxide, DMSO; citrate-dextrose solution, ACD)

– Participation in a concurrent interventional study