Mesenchymal Stromal Cells for Traumatic Brain Injury

Summary

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).

Conditions

• Traumatic Brain Injury With Loss of Consciousness

Interventions

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.

Sponsors & Collaborators

• Istituto Di Ricerche Farmacologiche Mario Negri

  collaborator OTHER

• A.O. Ospedale Papa Giovanni XXIII

  collaborator OTHER

• Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico

  collaborator OTHER

• Fondazione IRCCS San Gerardo dei Tintori

  lead OTHER

Principal Investigators

• Giuseppe Citerio, Professor · Fondazione IRCCS San Gerardo dei Tintori

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Model

PARALLEL

Eligibility

Min Age

18 Years

Max Age

70 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2023-09-19

Primary Completion

2024-12-31

Completion

2026-12-31

Countries

• Italy

Study Locations