RECRUITINGPhase 2INTERVENTIONAL

Mesenchymal Stromal Cells for Traumatic Brain Injury

MATRIx: MesenchymAl Stromal Cells for Traumatic bRain Injury

About This Trial

Traumatic Brain Injury (TBI) is an alteration of brain function caused by an external force. Long-term mortality in TBI is substantial, TBI survivors can develop chronic progressive disabilities and have a life expectancy shortened by 6 years. Treatment consists in supportive therapy directed at prevention of second insults, but no neuroprotective therapy is available. Given the multifaceted nature of TBI, mesenchymal stromal cells (MSCs) are an ideal candidate: they release multiple soluble factors shown to ameliorate the injury microenvironment through immunomodulatory, protective, reparative and regenerative processes. Preclinical data across a range of different TBI models and injury severities show that human MSCs improve outcome through pleiotropic mechanisms of protection and repair. Thus, data indicate MSCs as strong therapeutic candidate and support a clinical study in TBI. Aim: the study is designed to assess the safety and the efficacy of the MSCs, intravenously administered in severe TBI patients within 48h from injury. The study will be conducted in a stepwise manner. Step 1 will enroll 36 patients (randomized 1:1:1 in arms 80 x 10\^6 MSCs vs 160 x 10\^6 MSCs vs placebo) to define safety, and will allow to select the most promising dose. Step 2 will enroll 30 patients (1:1 in arms MSCs selected dose vs placebo) to define the MSC activity based on the quantification of the plasmatic levels of the neurofilament light (NFL) at 14 days, as biomarker of neuronal damage. Secondary objectives are aimed to assess: 1. brain injury evolution and white matter damage by longitudinal neuroimaging (at 4 days and 14 days post-TBI and at 6 months) 2. brain immunomodulatory changes by temporal profiling of circulating biomarkers of brain damage and neuroinflammation (daily for 3 days after TBI, at day 7 and 14, and at 1, 6 and 12 months) 3. clinical outcome by a structured clinical and neuropsychological assessment at both 6 and 12 months Methods: a multicenter, double blind, randomized, placebo-controlled, adaptive phase II dose finding study. Duration of the study: 36 months (24 of enrolment and 12 of follow up). Funding: Fondazione Regionale per la ricerca Biomedica, FRRB (Call "Unmet medical needs", proposal number 3440227) and Italian Ministry of health (Ministero della Salute, Bando di Ricerca Finalizzata 2021; proposal number RF-2021-12372642).

Who May Be Eligible (Plain English)

Who May Qualify: - Age: 18-70 years - Clinical frailty index (CFI) \< 5 - Evidence of TBI confirmed by abnormalities consistent with trauma on CT scan upon admission (Marshall's CT Classification \>1) - Feasibility of study drug (MSC/placebo) administration within 48 hours 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 Who Should NOT Join This Trial: - Motor GCS \> 5 at recruitment - High likelihood (\> 85%) of death in the first 48 h calculated by IMPACT calculator on early admission data - Bilateral mydriasis - Opening ICP \> 40 mmHg - Known history of prior brain injury, psychiatric disorder, neurological impairment and/or deficit - Brain penetrating injury - Spinal cord injury - Previous epilepsy requiring anti-convulsant therapy - Severe organ failure (including PaO2/FiO2\<200 and shock) - Recent serious infectious process - Cancer - Immunosuppression - Human weakened immune system virus - Positive urine pregnancy test or nursing - 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 Always talk to your doctor about whether this trial is right for you.

Original Eligibility Criteria

View original clinical language

Inclusion Criteria: * Age: 18-70 years * Clinical frailty index (CFI) \< 5 * Evidence of TBI confirmed by abnormalities consistent with trauma on CT scan upon admission (Marshall's CT Classification \>1) * Feasibility of study drug (MSC/placebo) administration within 48 hours 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 Exclusion Criteria: * Motor GCS \> 5 at recruitment * High likelihood (\> 85%) of death in the first 48 h calculated by IMPACT calculator on early admission data * Bilateral mydriasis * Opening ICP \> 40 mmHg * Known history of prior brain injury, psychiatric disorder, neurological impairment and/or deficit * Brain penetrating injury * Spinal cord injury * Previous epilepsy requiring anti-convulsant therapy * Severe organ failure (including PaO2/FiO2\<200 and shock) * Recent serious infectious process * Cancer * Immunosuppression * Human immunodeficiency virus * Positive urine pregnancy test or nursing * 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

Treatments Being Tested

DRUG

Mesenchymal stromal cell low dosage-80*10^6 cells

MSCs have to be administered at the dosage of 80\*10\^6. MSCs have to be administered by intravenous infusion via an in situ venous catheter within 15 minutes from the preparation and within 48 hours from TBI. They have to be diluted 1:2 in a saline solution for a total of 36mL.

DRUG

Mesenchymal stromal cell low dosage-160*10^6 cells

MSCs have to be administered at the dosage of 160\*10\^6. MSCs have to be administered by intravenous infusion via an in situ venous catheter within 15 minutes from the preparation and within 48 hours from TBI. They have to be diluted 1:2 in a saline solution for a total of 36mL.

OTHER

Placebo-storage solution

Placebo has to be administered by intravenous infusion via an in situ venous catheter within 15 minutes from the preparation and within 48 hours from TBI. It has to be diluted 1:2 in a saline solution for a total of 36mL.

Locations (3)

Fondazione IRCCS San Gerardo dei Tintori

Monza, MB, Italy

ASST Ospedale Papa Giovanni XXIII Bergamo

Bergamo, Italy

Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico of Milano

Milan, Italy