Protocol
Scientific title
Mesenchymal Stromal Cells for Traumatic Brain Injury
Health condition
Traumatic Brain Injury (TBI).
Orpha code 90056 (from https://www.malattierare.gov.it/)
Study Design
A multicenter, double blind, randomized, placebo controlled, adaptive phase II dose finding study.
The study is designed to assess the safety and the efficacy of theallogeneic bone marrow derived mesenchymal stromal cells (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 106 MSC vs 160 x 106 MSC vs placebo) to define safety and will allow to select themost promising dose. Step 2 will enroll 30 patients (1:1 in arms MSCselected dose vs placebo) to define the MSC activity based on the quantification of the plasmatic levels of the neurofilament light (NfL) at 14 days post TBI as biomarker of neuronal damage.
Background
TBI is an alteration of brain function caused by an external force. Every year, about 69 million people worldwide sustain a TBI. Long-term mortality in TBI is substantial, TBI survivors can develop chronic progressive disabilities and have a life expectancy shortenedby 6 years. Treatment consists in supportive therapy directed at prevention of secondary insults, but no neuroprotective therapy is available. Given the multifaceted nature of TBI, it is conceivable that multiple therapeutic targets may need to be addressedsimultaneously to interfere with the natural evolution of brain damage and improve patient’s outcome. In this contest, MSCs arean 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. Moreover, allogeneic MSCs have been used in more than 1000 clinical trials, and their systemic infusion has been proven safe in several pathological conditions. Thus, data indicate MSCs as strong therapeutic candidate and support a clinical study in TBI.
Study Aim and Objectives
The study is meant:
1. to define if allogeneic MSCs intravenously administered within48h from
injury at dosage of 80 or 160 x 106 cells are safe in patients withsevere TBI;
2. to define if MSCs administered at the dosage found to be safe and more promising in terms of activity as revealed by the interimanalysis decrease the plasmatic NfL biomarker of brain damage at 14 days post TBI compared to placebo treated patients.
Secondary objectives
1. brain injury evolution and white matter (WM) damage by longitudinal neuroimaging (at 4 days, 14 days and at 6 months post-TBI);
2. brain immunomodulatory changes by temporal profiling ofcirculating biomarkers of brain damage and neuroinflammation;
3. clinical outcome by a structured clinical and neuropsychological assessment at both 6 and 12 months.
Study Intervention
The investigational cellular product will be allogeneic unrelated donor human bone marrow derived MSCs intravenouslyadministered at dosage of 80 or 160 x 106 cells within 48 h after injury.
Patients enrolled in the control arm will be subjected to placebo administration, consisting in a solution containing the storage solution without cellular component.
The MSC and the placebo products will have identical appearance and consistency.
Primary Safety Outcome
The number of patients experiencing at least one serious adversedrug reaction (SADR).
Primary Efficacy Outcome
1. The number of responder patients, defined as patients whoreaches a NfL increase at 14 days equal or lower than 5-fold compared to baseline.
2. The quantitative blood NfL at Day 14 as measured by ultra-sensitive single-molecule array immunoassay (SIMOA).
Secondary Outcomes
1. Brain injury evolution and white matter damage by longitudinaladvanced magnetic resonance imaging (MRI) (performed at 4 days, 14 days and at 6 months post-TBI).
2. Brain immunomodulatory changes by temporal profiling ofcirculating biomarkers of:
a) structural damage: NfL, glial fibrillary acidic protein (GFAP)
b) neuroinflammation: interleukin-6 (IL-6), IL-10, tumor necrosis factor alpha (TNFα)
c) vascular integrity: matrix metallopeptidase 9 (MMP-9)
3. Clinical outcome by a structured clinical and neuropsychologicaloutcome assessment at both 6 and 12 months, by:
a) Glasgow Outcome Scale Extended (GOSE)
b) quality of life after brain injury (QOLIBRI) test
Inclusion and Exclusion Criteria
Inclusion criteria:
- Age: 18-70 years (inclusive)
- Clinical frailty index (CFI) < 5
- Evidence of TBI confirmed by abnormalities consistent with trauma on computed tomography (CT) scan upon admission (Marshall’s CT Classification >1)
- Study drug (MSC/placebo) administration start within 48 hours from TBI
- Glasgow Coma Scale (GCS) ≤ 8 at recruitment and at leastone pupil reactive to light
- Intracranial pressure (ICP) monitoring, already inserted orplanned for clinical indications
- Weight < 100 Kg and > 40 Kg
Exclusion criteria:
- Motor GCS > 5 at recruitment
- High likelihood (>85%) of death in the first 48h calculated byIMPACT (International Mission for Prognosis and Analysis of Clinical Trials in TBI) calculator on early admission data
- Bilateral unreactive mydriasis
- Opening ICP > 40 mmHg
- Known history of prior brain injury, psychiatric disorder,neurological impairment and/or deficit
- Brain penetrating injury
- Spinal cord injury
- Epilepsy requiring ongoing anti-convulsant therapy
- Severe organ failure (including PaO2/FiO2<200 and shock)
- Recent serious infections process requiring ICU admission
- Cancer (ongoing)
- Immunosuppression
- Human immunodeficiency virus (HIV)
- Positive urine pregnancy test or breastfeeding
- Known risk/history of coagulopathy and thromboembolism
- Pre-existing and severe ongoing:
§ lung disease (such as asthma, chronic obstructivepulmonary disease)
§ heart dysfunction (as heart failure and reduced cardiacoutput)
§ liver insufficiency (as cirrhosis)
§ kidney insufficiency
§ and other organ severe abnormalities
- Known hypersensitivity to excipients used in the formulation (Dimethyl sulfoxide, DMSO; Citrate-dextrose solution, ACD)
- Participation in a concurrent interventional study
Study Setting
Adult intensive care units.
Target Sample Size
The total number of evaluable patients to be analyzed will be 66 (27 on the control arm, 12 in the experimental arm stopping at first step and 27 in the experimental arm reaching the second step). In details, the total number of evaluable patients to be analyzed will be 24 (12 patients in each experimental arm) for the safety interim analysis and 54 for the final efficacy analysis (27 patients in both the control arm and in the experimental arm reaching the second step).
Follow-up duration
Patients will be monitored during routine visits up to 28 days post injury (if applicable). Late follow-up visits are planned at 6- and 12-months post-injury.
Statistical methods
The analysis of primary outcomes will be performed on the per-protocol (PP) population, including all randomized patients, without major violations of eligibility criteria, who received the allocated treatment as specified in the Protocol and with a follow-up of at least 14 days.
Safety outcome: the proportion of patients in each experimental group experiencing at least one SADR within 14 days from treatment administration will be described by means of frequency and percentages.
Efficacy outcome: the proportion of responder patients will be described by means of frequency and percentages. As primary analysis, a one-sided Student’s t-test on the logarithmic scale will be performed in order to compare the NfL measured at 14 days from baseline between the experimental and control arms.
Analysis of the secondary outcomes: univariable and multivariable generalized linear mixed regression models for repeated measures will be used to evaluate the impact of treatment on longitudinal MRI, blood biomarkers, and functional outcome.
Expected results
We expect to prove the safety and efficacy of MSC intravenous administration in acute and severe TBI patients. We will provide a detailed longitudinal description of the effects of MSCs on brain advanced neuroimaging trajectories, on axonal damage and neuro-immunomodulatory changes by blood biomarker analysis and on clinical outcome. Success in this project will pave the way for a subsequent phase III trial to test MSC efficacy on neurological outcome in severe TBI.
Study duration
36 months (which includes 12 months of follow up)
The full protocol is available on reasonable request to matrix@unimib.it