Clinical trial NCT06146062: 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.
Official title: 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 type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Traumatic Brain Injury
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2023-11-24
Enrollment: 68
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: effect of iterative IV injections of WJ-UC-MSC on post-traumatic neuroinflammation
timeFrame: 6 months after the last injection
Secondary outcomes:
measure: radiological markers from PET-MRI_1
timeFrame: 6 months after the last injection
measure: radiological markers from PET-MRI_2
timeFrame: 6 months after the last injection
measure: Treatment feasibility
timeFrame: at the third injection
measure: Neurological clinical Score M6
timeFrame: 6 months after the last injection
measure: Neurological clinical Score M12
timeFrame: 12 months after the last injection
measure: cognitive assessment M6
timeFrame: 6 months after the last injection
measure: cognitive assessment M12
timeFrame: 12 months after the last injection
measure: short term Tolerance D10
timeFrame: 10 days after the last injection
measure: long term Tolerance M6
timeFrame: 6 months after the last injection
measure: long term Tolerance M12
timeFrame: 6 months after the last injection
measure: neuroinflammation of pericontusional
timeFrame: 6 months after the last injection
measure: neuroinflammation of grey matter
timeFrame: 6 months after the last injection
measure: neuroinflammation of white matter
timeFrame: 6 months after the last injection
measure: neuroinflammation of frontal area
timeFrame: 6 months after the last injection
measure: neuroinflammation of parietal area
timeFrame: 6 months after the last injection
measure: neuroinflammation of occipital area
timeFrame: 6 months after the last injection
measure: neuroinflammation of hippocampus
timeFrame: 6 months after the last injection
measure: neuroinflammation of thalamus
timeFrame: 6 months after the last injection
measure: neuroinflammation of mesencephalus
timeFrame: 6 months after the last injection
measure: neuroinflammation of cerebellum
timeFrame: 6 months after the last injection
measure: Cytokine and chemokine levels in plasma
timeFrame: 6 months after the last injection
measure: PBMC profile
timeFrame: 6 months after the last injection
measure: Transcriptomics and regulatory epigenomics of circulating monocytes and lymphocytes 1.
timeFrame: 6 months after the last injection
measure: Transcriptomics and regulatory epigenomics of circulating monocytes and lymphocytes 2.
timeFrame: 6 months after the last injection
measure: Transcriptomics and regulatory epigenomics of circulating monocytes and lymphocytes 3.
timeFrame: 6 months after the last injection
measure: Transcriptomics and regulatory epigenomics of circulating monocytes and lymphocytes 4.
timeFrame: 6 months after the last injection
measure: Genome-wide single-nucleotide polymorphism (SNP) genotype.
timeFrame: After 1 injection
Other outcomes:
measure: Analyze the pharmacokinetics and pharmacodynamics of CSM WJ-UC in humans 1
timeFrame: After 3rd injection 48 hours later
measure: Analyze the pharmacokinetics and pharmacodynamics of CSM WJ-UC in humans 2
timeFrame: After 3rd injection 48 hours later
measure: Deep phenotyping of the main immune effector cell populations humans, to identify the phenotypes involved in immunomodulation and alloimmunization induced by MSC administration. 1
timeFrame: After 3rd injection 48 hours later
measure: Deep phenotyping of the main immune effector cell populations humans, to identify the phenotypes involved in immunomodulation and alloimmunization induced by MSC administration.2
timeFrame: After 3rd injection 48 hours later
measure: Deep phenotyping of the main immune effector cell populations humans, to identify the phenotypes involved in immunomodulation and alloimmunization induced by MSC administration.3
timeFrame: After 3rd injection 48 hours later
measure: Deep phenotyping of the main immune effector cell populations humans, to identify the phenotypes involved in immunomodulation and alloimmunization induced by MSC administration. 4
timeFrame: After 3rd injection 48 hours later
measure: Deep phenotyping of the main immune effector cell populations humans, to identify the phenotypes involved in immunomodulation and alloimmunization induced by MSC administration. 5
timeFrame: After 3rd injection 48 hours later
measure: Deep phenotyping of the main immune effector cell populations humans, to identify the phenotypes involved in immunomodulation and alloimmunization induced by MSC administration. 6
timeFrame: After 3rd injection 48 hours later
measure: Deep phenotyping of the main immune effector cell populations humans, to identify the phenotypes involved in immunomodulation and alloimmunization induced by MSC administration. 7
timeFrame: After 3rd injection 48 hours later
measure: Deep phenotyping of the main immune effector cell populations humans, to identify the phenotypes involved in immunomodulation and alloimmunization induced by MSC administration. 8
timeFrame: After 3rd injection 48 hours later
Locations:
city: Clamart
country: France
facility: Hôpital National d'Instruction des Armées Percy
city: Clichy
country: France
facility: Beaujon Hospital
city: Paris
country: France
facility: Hôpital de la Pitié Salpêtrière - AP-HP
Study officials:
affiliation: APHP
name: Vincent DEGOS
role: PRINCIPAL_INVESTIGATOR
References: