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.

NCT ID: NCT06146062

Last Updated: 2024-10-16

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 68 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-06-25
• Study Completion Date: 2028-03-31

Brief Summary

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

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.

Conditions

Traumatic Brain Injury

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

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.

Group Type: EXPERIMENTAL

Mesenchymal Stromal Cells (MSC)

Intervention Type: DRUG

3 injections one week apart

control

The placebo will be a solution of NaCl 0.9% 3 injections one week apart.

Group Type: PLACEBO_COMPARATOR

placebo

Intervention Type: DRUG

3 injections one week apart

Interventions

Mesenchymal Stromal Cells (MSC)

3 injections one week apart

Intervention Type: DRUG

placebo

3 injections one week apart

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

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

• 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

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

• 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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 50 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Assistance Publique - Hôpitaux de Paris

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Vincent DEGOS

Role: PRINCIPAL_INVESTIGATOR

APHP

Locations

Hôpital National d'Instruction des Armées Percy

Clamart, , France

Site Status: RECRUITING

Beaujon Hospital

Clichy, , France

Site Status: RECRUITING

Hôpital de la Pitié Salpêtrière - AP-HP

Paris, , France

Site Status: RECRUITING

Countries

France

Central Contacts

Vincent Degos

Role: CONTACT

vincent.degos@aphp.fr

142163761 ext. 33

Stéphanie Sigaut

Role: CONTACT

stephanie.sigaut@aphp.fr

140875009 ext. 33

Facility Contacts

Mathieu BOUTONNET

Role: primary

BOUTONNET Mathieu

Role: backup

Stéphanie SIGAUT

Role: primary

DEGOS Vincent

Role: primary

References

Sigaut S, Tardivon C, Jacquens A, Bottlaender M, Gervais P, Habert MO, Monsel A, Roquilly A, Boutonnet M, Galanaud D, Cras A, Boucher-Pillet H, Florence AM, Cavalier I, Menasche P, Degos V, Couffignal C. 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): study protocol for a multicentre randomised controlled trial. BMJ Open. 2024 Dec 31;14(12):e091441. doi: 10.1136/bmjopen-2024-091441.

Reference Type: DERIVED

PMID: 39740941 (View on PubMed)

Other Identifiers

2021-006873-50

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

APHP211509

Identifier Type: -

Identifier Source: org_study_id