Clinical Research Directory

Intranasal Stem Cells to Treat Perinatal Brain Injury to Combat Cerebral Palsy

Hypoxic-ischemic brain injury (HIBI) is a leading cause of death and lifelong disability in near-term and term infants, most often caused by perinatal arterial ischemic stroke (PAIS, incidence approximately 1:5000 live births) or perinatal asphyxia (PA, incidence 1-2:1000 live births). No treatment currently exists to repair or limit HIBI, and many affected infants go on to develop cerebral palsy, cognitive impairment, epilepsy, or visual or hearing deficits. Intranasally administered bone marrow-derived mesenchymal stromal cells (IN-MSC) are a candidate regenerative therapy for HIBI. Preclinical studies show that IN-MSC migrate to injured brain regions, dampen neuroinflammation, and stimulate endogenous neural repair, improving both structural and functional outcomes in animal models of HIBI. A first-in-human phase I trial (PASSIoN) in 10 neonates with PAIS showed that intranasal MSC administration was feasible and well tolerated, with no serious adverse events and promising early efficacy signals at 2-year follow-up. iSTOP-CP is a phase II, single-center (UMC Utrecht, the Netherlands), double-blind, randomized, placebo-controlled trial evaluating whether IN-MSC therapy can prevent or reduce motor and other disabilities in infants with MRI-confirmed HIBI due to PAIS or PA. Eligible infants are born at 35.0 weeks of gestation or later, have HIBI confirmed on brain MRI or MRS in predefined brain regions predictive of poor outcome, and are diagnosed with PAIS or PA, with or without prior therapeutic hypothermia. A total of 162 infants will be randomized 1:1 to IN-MSC or matching placebo, stratified by the cause of HIBI and, within the PAIS group, by stroke territory. Infants with suspected chromosomal, metabolic, or congenital central nervous system anomalies, intracranial hemorrhage as the main injury, or contraindications to intranasal administration are excluded, as are infants for whom the clinical team has decided to withdraw intensive care. Participants receive a single intranasal dose of bone marrow-derived MSC or a visually indistinguishable placebo within 7 days after birth. Participants are followed for 24 months, with neurodevelopmental follow-up visits at 3-4, 6, 9-12, and 24 months of age and a brain MRI at 52 weeks postmenstrual age. The primary endpoint is the motor composite score of the Dutch version of the Bayley Scales of Infant and Toddler Development, 4th edition (Bayley-IV-NL), assessed at 24 months corrected age. Key secondary endpoints include cognitive development, the incidence of sensorineural disability, neuroregenerative imaging biomarkers, safety, health-related quality of life for infants and their parents, and the cost-effectiveness of IN-MSC treatment, evaluated through a health technology assessment.

Cerebral Oximetry in Management of Post Cardiac Arrest

Resuscitation from a cardiac arrest is a common reason for admission to an intensive care unit (ICU). Because the brain is highly vulnerable to oxygen deprivation, severe brain damage often occurs during a cardiac arrest. Even when the heart has been restarted, there may continue to be reduced blood flow and oxygen delivery to the brain for many hours. ICU professionals generally do not use any tools to detect low oxygen delivery to the brain. Most patients admitted to the ICU are initially in a coma and many will never awaken. Even if they regain consciousness, there may be long-term cognitive and functional disabilities. There are currently no specific treatments available to ICU professionals that are proven to limit brain damage and improve outcomes. Cerebral oximetry is a non-invasive, painless, safe, and easy-to-use tool that detects reduced oxygen delivery to the brain using a sensor over the forehead. Previous research shows that reduced brain oxygen levels \[(regional oxygen saturation (RSO2)\] are predictive of a lower chance of awakening and having a good neurological recovery. This study will assess treatment guided by cerebral oximetry during the initial 48 hours following cardiac arrest. Patients that are in a coma after their circulation has been restarted will be randomly allocated to either usual care based on international guidelines or a protocol aimed at maintaining RSO2 above 60% on both sides of the brain. Cerebral oximetry will be recorded in all patients, but doctors will only be aware of it in one group. If RSO2 drops below 60% for more than 5 minutes, doctors will try to increase it. Actions taken to increase RSO2 may include raising the blood pressure by giving more intravenous fluid or using life-support drugs ("vasoconstrictors" like norepinephrine), stimulating the heart to pump more strongly with medications ("inotropes" like dobutamine, milrinone, or epinephrine), adjusting ventilator settings (to increase the amount of oxygen dissolved in blood or raise carbon dioxide levels, which increases blood flow to the brain), lowering the head of the bed (to increase blood flow to the brain), or giving a blood transfusion (only if the patient has anemia). When RSO2 has been corrected to at least 60% for more than 2 hours, doctors may reverse previous interventions. If they are unable to achieve the goal of 60%, they may lower the target. Efforts to maintain RSO2 in the target range will continue for 48 hours. Investigators will assess how well the protocol works and whether it helps avoid critically low brain oxygen levels. Investigators will also measure various "biomarkers" in the blood that are released when the brain is damaged to see if they are lower when cerebral oximetry is used to guide treatment.

Multiomics Profiling of CSF in Cardiac Arrest Survivors

The goal of this observational study is to identify further pathophysiologic mechanism of secondary brain injury following cardiac arrest by using serial multiomics profiling of serum and cerebrospinal fluid (CSF) samples. The main question it aims to answer is: A. The main question it aims to answer is: What are the dynamic molecular changes in serum and CSF that reflect the pathophysiological mechanisms of secondary brain injury after cardiac arrest? B. What are the differences in serum and CSF multiomic signatures between varying severities of cardiac arrest, and how are these differences associated with the underlying pathophysiological mechanisms of secondary brain injury? Serum and CSF samples that have already been prospectively collected from participants and stored in the BioBank will be used for this analysis.

Molecular Insights Into Post-Cardiac Arrest Brain Injury Via CSF Multi-Omics

The goal of this study is to uncover the molecular mechanisms responsible for secondary brain injury in patients with post-cardiac arrest syndrome by analyzing cerebrospinal fluid (CSF) using multi-omics techniques. The main question this study aims to answer is: Which genome-, transcriptome-, proteome-, and metabolome-level changes in CSF are associated with secondary brain injury after cardiac arrest? To address this question, CSF samples collected from post-cardiac arrest patients will undergo multi-omics analyses. Identified molecular pathways will be used to screen existing drug databases and generate new therapeutic candidates through computational modeling and compound synthesis. These findings will provide the scientific foundation needed to design and implement future preclinical experiments using cardiac arrest animal models.

Regional Ventilation Evaluation During Neuro-injury Weaning Study

This study evaluates changes in regional lung ventilation using thoracic electrical impedance tomography (EIT) during the weaning process from mechanical ventilation in ICU patients with acute brain injury. It aims to identify predictive EIT patterns related to extubation outcomes.

Identification of Brain Injury Using Portable MRI

The goal of this study is to look for brain injury in patients who had a cardiac arrest, using portable brain imaging. The portable nature of this test will also allow for serial imaging so the investigators can understand how brain injury changes over days. The results of this study may allow for bedside imaging to be available at centers without specialized imaging centers and may identify markers of brain injury that help to select the patients most likely to benefit for clinical trials.