Effects of Intravascular Administration of Mesenchymal Stromal Cells Derived From Wharton's Jelly of the Umbilical Cord on Systemic Immunomodulation and Neuroinflammation After Traumatic Brain Injury.

Study Overview
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Brief Summary
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Traumatic brain injuries (TBI) are one of the leading causes of death and disability worldwide. These patients are burdened by physical, cognitive, and psychosocial deficits, leading to an important economic impact for society. Treatments for TBI patients are limited and none has been shown to provide prolonged and long-term neuroprotective or neurorestorative effects. TBI related disability is linked to the severity of the initial injury but also to the following neuroinflammatory response which may persist long after the initial injury. Moreover, a growing body of evidence suggests a link between TBI-induced neuro-inflammation and neurodegenerative post traumatic disorders. Consequently, new therapies triggering immunomodulation and promoting neurological recovery are the subject of major research efforts. In this context, mesenchymal cell-based therapies are currently investigated to treat various neurological disorders due to their ability to modulate neuroinflammation and to promote simultaneous neurogenesis, angiogenesis, and neuroprotection. Clinical trials using intravenous MSC have been conducted for various pathologies, all these studies showing a good safety profile. The hypothesis of the study is that intravenous repeated treatment with MSC derived from Wharton's Jelly of the umbilical cord may be associated with a significant decrease of post-TBI neuroinflammation and improvement of neuroclinical status. The main objective of the study is to evaluate the effect of iterative IV injections of MSC on post-traumatic neuroinflammation measured in corpus callosum by PET-MRI at 6 months in severe brain injured patients unresponsive to simple verbal commands 5 days after sedation discontinuation.

Detailed Description
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Traumatic brain injuries (TBI) are one of the leading causes of death and disability worldwide. These patients are burdened by physical, cognitive, and psychosocial deficits, leading to an important economic impact for society. Treatments for TBI patients are limited and none has been shown to provide prolonged and long-term neuroprotective or neurorestorative effects. TBI related disability is linked to the severity of the initial injury but also to the following neuroinflammatory response which may persist long after the initial injury. Moreover, a growing body of evidence suggests a link between TBI-induced neuro-inflammation and neurodegenerative post traumatic disorders. Consequently, new therapies triggering immunomodulation and promoting neurological recovery are the subject of major research efforts. In this context, mesenchymal cell-based therapies are currently investigated to treat various neurological disorders due to their ability to modulate neuroinflammation and to promote simultaneous neurogenesis, angiogenesis, and neuroprotection. Indeed, several experimental studies have reported that human umbilical cord-derived mesenchymal stromal cells (MSC) have the ability to improve neurological outcomes and recovery in cerebral injury animal models, including TBI. Clinical trials using intravenous MSC have been conducted for various pathologies, all these studies showing a good safety profile. In TBI, small clinical trials using different modalities for administration of mesenchymal cells are available but none about MSC derived from Wharton's Jelly of the umbilical cord. The hypothesis of the study is that intravenous repeated treatment with MSC derived from Wharton's Jelly of the umbilical cord may be associated with a significant decrease of post-TBI neuroinflammation and improvement of neuroclinical status. The main objective of the study is to evaluate the effect of iterative IV injections of MSC on post-traumatic neuroinflammation measured in corpus callosum by PET-MRI at 6 months in severe brain injured patients unresponsive to simple verbal commands 5 days after sedation discontinuation.

Official Title
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Effects of Intravascular Administration of Mesenchymal Stromal Cells Derived From Wharton's Jelly of the Umbilical Cord on Systemic Immunomodulation and Neuroinflammation After Traumatic Brain Injury.

Conditions
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Traumatic Brain Injury

Intervention / Treatment
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* Drug: Mesenchymal Stromal Cells (MSC)
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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20 healthy volunteers will be included for MRI normalization Inclusion Criteria: Age 18-50 years Severe TBI defined by: Glasgow score <12 within the 48 first hours, brain lesion on CT scan, Need for intracranial pressure monitoring Unresponsive to verbal commands 5 days after sedation discontinuation, for whom, after usual clinical and paraclinical evaluation there has been no decision to interrupt active therapies within 10 days after sedation discontinuation Written consent signed by the close relative Exclusion Criteria: History of disease or treatment impairing current or previous year immunity function History of severe neurological or psychiatric disease likely to alter neurological assessment HTAP > grade III OMS/WHO Ongoing uncontrolled infection with organ failure (septic shock, ARDS) including those due to severe COVID-19 Platelets <100,000 G/L, Hb <8 g/dL, lymphocytes count <1500 G/L, neutrophils count <2,500G/L, creatinin > 100 μmol/L Liver function abnormalities (bilirubin> 2.5mg / dL or transaminases> 5x the ULN). Patients with Gilbert's disease are eligible if liver tests are normal excluding bilirubinemia Known HIV seropositivity Neoplasia ongoing or treated in the 3 years before screening Bone marrow transplant recipient History of transfusion reaction or hypersensitivity Pregnancy Contraindication for MRI and PET-MRI: Patient with Pacemaker and defibrillator MR-incompatible prosthetic heart valve Metallic intraocular, intra cerebral or intra medullary foreign bodies Implantable neurostimulation systems Cochlear implants/ ear implant Metallic fragments such as bullets, shotgun pellets, and metal shrapnel Cerebral artery aneurysm clips Ventriculo peritoneal shunt with metallic component generating significant artefacts on the MR sequence Catheters with metallic components (Swan-Ganz catheter) Patient unable to remain supine and motionless during the duration of the examination Participation in another interventional clinical trial of an investigational therapy within 30 days of consent No affiliation to a social security regime Vulnerable person according to article L1121-6 of the CSP Protected adult person

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention<br>Final product is a MSC solution at the concentration of 2.106/kg in 150 mL of NaCl 0.9% and human albumin 0.5%, conditioned aseptically and identified for IV administration. 3 injections one week apart. | Drug: Mesenchymal Stromal Cells (MSC)<br>* 3 injections one week apart<br>|
| Placebo Comparator: control<br>The placebo will be a solution of NaCl 0.9% 3 injections one week apart. | Drug: placebo<br>* 3 injections one week apart<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| effect of iterative IV injections of WJ-UC-MSC on post-traumatic neuroinflammation | [18F]-DPA-714 Standard Uptake Value ratio (SUVr) in corpus callosum (Region of Interest, ROI) measured by dynamic PET-MRI | 6 months after the last injection | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| radiological markers from PET-MRI_1 | The regional fractional anisotropy (FA) from DTI acquisition of PET-MRI | 6 months after the last injection | 
| radiological markers from PET-MRI_2 | The mean diffusibility (MD) from DTI acquisition of PET-MRI | 6 months after the last injection | 
| Treatment feasibility | number of treatments administrated to the patient | at the third injection | 
| Neurological clinical Score M6 | Glasgow Outcome Scale-Extended | 6 months after the last injection | 
| Neurological clinical Score M12 | Glasgow Outcome Scale-Extended | 12 months after the last injection | 
| cognitive assessment M6 | MOCA scale | 6 months after the last injection | 
| cognitive assessment M12 | MOCA scale | 12 months after the last injection | 
| short term Tolerance D10 | Common Terminology Criteria for Adverse Events | 10 days after the last injection | 
| long term Tolerance M6 | Common Terminology Criteria for Adverse Events | 6 months after the last injection | 
| long term Tolerance M12 | Common Terminology Criteria for Adverse Events | 6 months after the last injection |