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. (TRAUMACELL)

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.

Study Overview

• Status: Recruiting
• Conditions: Traumatic Brain Injury
• Intervention / Treatment: Drug: Mesenchymal Stromal Cells (MSC); Drug: placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 68
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Vincent Degos; Phone Number: 33 142163761; Email: vincent.degos@aphp.fr
• Study Contact Backup: Name: Stéphanie Sigaut; Phone Number: 33 140875009; Email: stephanie.sigaut@aphp.fr

Study Locations

• France
  • Clamart, France
    • Recruiting
    • Hôpital National d'Instruction des Armées Percy
    • Contact: Mathieu BOUTONNET
    • Contact: BOUTONNET Mathieu
  • Clichy, France
    • Recruiting
    • Beaujon Hospital
    • Contact: Stéphanie SIGAUT
  • Paris, France
    • Recruiting
    • Hôpital de la Pitié Salpêtrière - AP-HP
    • Contact: DEGOS Vincent

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

20 healthy volunteers will be included for MRI normalization Volunteer eligibility criteria

Inclusion criteria :

• Age 18-50 years
• ASA 1 classification (healthy patient)

Exclusion criteria :

• Lack of written consent
• Neurological history likely to alter the image (epilepsy, transient ischaemic attack, meningitis, head trauma)
• Vulnerable person according to article L1121-6 of the CSP
• Protected adult person
• No affiliation to a social security regime
• Pregnancy

• Contraindication for MRI and PET-MRI

  • patients 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

    68 severe TBI patients with the following inclusion and exclusion criteria will be included"

Patient Inclusion criteria

• Age 18-50 years

• Severe TBI defined by:

  • Glasgow score <12 within the 48 first hours,
  • Brain traumatic lesion on CT scan,
  • Need for intracranial pressure monitoring
• No other significant organ trauma (AIS <2)
• 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

Patient Exclusion criteria

• History of disease or treatment impairing current or previous year immunity function ( hematologic disease (leukemia, myeloma), viral disease affecting immunity (like HIV), immunological treatment (corticoid, anti rejection medication, anti TNFα, chemotherapy)
• 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 G/L or <100000/μL, Hb <8 g/dL, lymphocytes count <1.5 G/L or 1500 μL , neutrophils count < 2.5G/L or <2500/μL, , 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 o Metallic intraocular, intra cerebral or intra medullary foreign bodies
  • Implantable neurostimulation systems o 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: control; The placebo will be a solution of NaCl 0.9% 3 injections one week apart.	Drug: placebo; 3 injections one week apart
Experimental: Intervention; Final product is a MSC solution at the concentration of 2.10^6/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); 3 injections one week apart

What is the study measuring?

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
neuroinflammation of pericontusional	[18F]-DPA-714 Standard Uptake Value ratio (SUVr) in pericontusional	6 months after the last injection
neuroinflammation of grey matter	[18F]-DPA-714 Standard Uptake Value ratio (SUVr) in grey matter	6 months after the last injection
neuroinflammation of white matter	[18F]-DPA-714 Standard Uptake Value ratio (SUVr) in white matter	6 months after the last injection
neuroinflammation of frontal area	[18F]-DPA-714 Standard Uptake Value ratio (SUVr) in frontal area	6 months after the last injection
neuroinflammation of parietal area	[18F]-DPA-714 Standard Uptake Value ratio (SUVr) in parietal area	6 months after the last injection
neuroinflammation of occipital area	[18F]-DPA-714 Standard Uptake Value ratio (SUVr) in occipital area	6 months after the last injection
neuroinflammation of hippocampus	[18F]-DPA-714 Standard Uptake Value ratio (SUVr) in hippocampus,	6 months after the last injection
neuroinflammation of thalamus	[18F]-DPA-714 Standard Uptake Value ratio (SUVr) in thalamus,	6 months after the last injection
neuroinflammation of mesencephalus	[18F]-DPA-714 Standard Uptake Value ratio (SUVr) in mesencephalus	6 months after the last injection
neuroinflammation of cerebellum	[18F]-DPA-714 Standard Uptake Value ratio (SUVr) in cerebellum	6 months after the last injection
Cytokine and chemokine levels in plasma	Luminex magnetic beads technology	6 months after the last injection
PBMC profile	High-dimensional characterization of immune reprogramming during the treatment by single-cell RNA-sequencing of PBMC.	6 months after the last injection
Transcriptomics and regulatory epigenomics of circulating monocytes and lymphocytes 1.	H3K27ac	6 months after the last injection
Transcriptomics and regulatory epigenomics of circulating monocytes and lymphocytes 2.	H3K4me3	6 months after the last injection
Transcriptomics and regulatory epigenomics of circulating monocytes and lymphocytes 3.	ChIP-seq	6 months after the last injection
Transcriptomics and regulatory epigenomics of circulating monocytes and lymphocytes 4.	ATAC-seq	6 months after the last injection
Genome-wide single-nucleotide polymorphism (SNP) genotype.	DNA sample	After 1 injection

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Analyze the pharmacokinetics and pharmacodynamics of CSM WJ-UC in humans 1	NGS approach,	After 3rd injection 48 hours later
Analyze the pharmacokinetics and pharmacodynamics of CSM WJ-UC in humans 2	digital droplet (dd)-PCR approach,	After 3rd injection 48 hours later
Deep phenotyping of the main immune effector cell populations humans, to identify the phenotypes involved in immunomodulation and alloimmunization induced by MSC administration. 1	populations of immune effector cells, such as Tregs,	After 3rd injection 48 hours later
Deep phenotyping of the main immune effector cell populations humans, to identify the phenotypes involved in immunomodulation and alloimmunization induced by MSC administration.2	populations of immune effector cells, such as Teff,	After 3rd injection 48 hours later
Deep phenotyping of the main immune effector cell populations humans, to identify the phenotypes involved in immunomodulation and alloimmunization induced by MSC administration.3	populations of immune effector cells, such as NK cells,	After 3rd injection 48 hours later
Deep phenotyping of the main immune effector cell populations humans, to identify the phenotypes involved in immunomodulation and alloimmunization induced by MSC administration. 4	populations of immune effector cells, such as NKT,	After 3rd injection 48 hours later
Deep phenotyping of the main immune effector cell populations humans, to identify the phenotypes involved in immunomodulation and alloimmunization induced by MSC administration. 5	populations of immune effector cells, such as MAIT,	After 3rd injection 48 hours later
Deep phenotyping of the main immune effector cell populations humans, to identify the phenotypes involved in immunomodulation and alloimmunization induced by MSC administration. 6	populations of immune effector cells, such as DC	After 3rd injection 48 hours later
Deep phenotyping of the main immune effector cell populations humans, to identify the phenotypes involved in immunomodulation and alloimmunization induced by MSC administration. 7	populations of immune effector cells, such as monocytes	After 3rd injection 48 hours later
Deep phenotyping of the main immune effector cell populations humans, to identify the phenotypes involved in immunomodulation and alloimmunization induced by MSC administration. 8	populations of immune effector cells, such as B cells.	After 3rd injection 48 hours later

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Vincent DEGOS, APHP

Study record dates

Study Major Dates

• Study Start (Actual): June 25, 2024
• Primary Completion (Estimated): August 31, 2027
• Study Completion (Estimated): March 31, 2028

Study Registration Dates

• First Submitted: November 17, 2023
• First Submitted That Met QC Criteria: November 17, 2023
• First Posted (Actual): November 24, 2023

Study Record Updates

• Last Update Posted (Actual): October 16, 2024
• Last Update Submitted That Met QC Criteria: October 14, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Inflammation; Craniocerebral Trauma; Trauma, Nervous System; Brain Injuries; Wounds and Injuries; Brain Injuries, Traumatic; Neuroinflammatory Diseases
• Other Study ID Numbers: APHP211509; 2021-006873-50 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No