MATRIx: MesenchymAl Stromal Cells for Traumatic bRain Injury
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 78
- 试验地点
- 3
- 主要终点
- safety of mesenchimal stromal cell intravenous administration in TBI patients
研究概览
简要总结
Traumatic Brain Injury (TBI) is an alteration of brain function caused by an external force. Long-term mortality in TBI is substantial, TBI survivors can develop chronic progressive disabilities and have a life expectancy shortened by 6 years. Treatment consists in supportive therapy directed at prevention of second insults, but no neuroprotective therapy is available. Given the multifaceted nature of TBI, mesenchymal stromal cells (MSCs) are an 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. Thus, data indicate MSCs as strong therapeutic candidate and support a clinical study in TBI.
Aim: the study is designed to assess the safety and the efficacy of the 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 10^6 MSCs vs 160 x 10^6 MSCs vs placebo) to define safety, and will allow to select the most promising dose. Step 2 will enroll 30 patients (1:1 in arms MSCs selected dose vs placebo) to define the MSC activity based on the quantification of the plasmatic levels of the neurofilament light (NFL) at 14 days, as biomarker of neuronal damage.
Secondary objectives are aimed to assess:
- brain injury evolution and white matter damage by longitudinal neuroimaging (at 4 days and 14 days post-TBI and at 6 months)
- brain immunomodulatory changes by temporal profiling of circulating biomarkers of brain damage and neuroinflammation (daily for 3 days after TBI, at day 7 and 14, and at 1, 6 and 12 months)
- clinical outcome by a structured clinical and neuropsychological assessment at both 6 and 12 months
Methods: a multicenter, double blind, randomized, placebo-controlled, adaptive phase II dose finding study.
Duration of the study: 36 months (24 of enrolment and 12 of follow up).
Funding: Fondazione Regionale per la ricerca Biomedica, FRRB (Call "Unmet medical needs", proposal number 3440227) and Italian Ministry of health (Ministero della Salute, Bando di Ricerca Finalizzata 2021; proposal number RF-2021-12372642).
详细描述
Study Description: Multicenter, double blind, randomized, placebo-controlled, adaptive phase II dose finding study meant to define if MSCs, administered at dosage of 80 or 160 x 10^6 cells within 48h from TBI, are safe in patients with severe TBI, and to define if MSCs, administered at the dosage found to be safe and more promising, decrease the plasmatic neurofilament light (NFL) biomarker of brain damage at 14 days. Patients will be recruited at the Neurointensive Care Unit at Fondazione IRCCS San Gerardo dei Tintori, Monza, at ASST Ospedale Papa Giovanni XXIII Bergamo and at Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico of Milano. Collection of multiple clinical, neuroimaging and biological parameters will describe TBI evolution.
Preclinical studies: Studies in rodent TBI models have shown that administration of MSCs produces functional improvement with amelioration of sensorimotor and cognitive deficit, reduction of contusion volume and neuronal loss, modulation of the inflammatory response with decreased inflammation, stimulation of beneficial endogenous mechanisms (angiogenesis, neurogenesis, synaptic plasticity). These results support the notion that MSCs can reprogram the microenvironment mitigating the progression of brain damage and fostering recovery of function. Only few clinical studies have assessed the safety, feasibility and efficacy of MSC therapy. No adverse events (AEs) or severe adverse events (SAEs) were reported. No AEs were associated to the intravenous route, which is the one the investigators propose for the study.
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).
Expecting a 13% of deaths of TBI patients in ICU, the number of patients to be randomized is about 78 (32 in the control arm, 14 in the experimental arm stopping at first step and 32 in the experimental arm reaching the second step). In case of the trial closure after the first step, the number of patients to randomize will be about 42 (14 in each arm).
Statistical design and sample size:The statistical study design is conceived in 2 steps.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age: 18-70 years
- •Clinical frailty index (CFI) < 5
- •Evidence of TBI confirmed by abnormalities consistent with trauma on CT scan upon admission (Marshall's CT Classification >1)
- •Feasibility of study drug (MSC/placebo) administration within 48 hours from TBI
- •GCS ≤ 8 at recruitment and at least one pupil reactive to light
- •ICP monitoring already inserted or planned for clinical indications
- •Weight < 100 Kg and > 40 kg
排除标准
- •Motor GCS > 5 at recruitment
- •High likelihood (> 85%) of death in the first 48 h calculated by IMPACT calculator on early admission data
- •Bilateral mydriasis
- •Opening ICP > 40 mmHg
- •Known history of prior brain injury, psychiatric disorder, neurological impairment and/or deficit
- •Brain penetrating injury
- •Spinal cord injury
- •Previous epilepsy requiring anti-convulsant therapy
- •Severe organ failure (including PaO2/FiO2<200 and shock)
- •Recent serious infectious process
- •Immunosuppression
- •Human immunodeficiency virus
- •Positive urine pregnancy test or nursing
- •Known risk/history of coagulopathy and thromboembolism
- •Pre-existing and severe:
- •lung disease (such as asthma, chronic obstructive pulmonary disease),
- •heart dysfunction (as heart failure and reduced cardiac output),
- •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
研究组 & 干预措施
1-control (placebo)
Administration: once (bolus), intravenous, 36mL
干预措施: Placebo-storage solution (Other)
2-MSCs 80*10^6
Administration: once (bolus), intravenous, 36mL
干预措施: Mesenchymal stromal cell low dosage-80*10^6 cells (Drug)
3-MSCs 160*10^6
Administration: once (bolus), intravenous, 36mL
干预措施: Mesenchymal stromal cell low dosage-160*10^6 cells (Drug)
结局指标
主要结局
safety of mesenchimal stromal cell intravenous administration in TBI patients
时间窗: 14 days from treatment administration
number of patients in each of the two experimental dosage group experiencing at least one serious adverse drug reaction (SADR) (assessed by CTCAE v5.0) within 14 days from treatment. The maximum number of patients experiencing at least one SADR to observe in each experimental group is 1 out of 12.
efficacy of mesenchimal stromal cells in preventing subacutely post-TBI brain axonal injury
时间窗: 14 days post-TBI
number of MSC-treated patients who reach a plasmatic NFL (neurofilament light) increase at 14 days post-treatment equal or lower than 5-fold compared to the baseline (these patients are defined as "responder patients")
次要结局
- efficacy of mesenchimal stromal cells in preventing the plasmatic increase of TBI-related circulating biomarkers(daily for 3 days after TBI, at day 7 and 14, and at 1, 6 and 12 months)
- efficacy of mesenchimal stromal cells in preventing post-TBI brain anatomical injury(4 days post-TBI, 14 days and 6 months)
- efficacy of mesenchimal stromal cell administration in improving the clinical outcome of TBI patients(6 and 12 months post-TBI)