Hypoxic-Ischemic Encephalopathy

Hypoxic-Ischemic Encephalopathy (HIE) occurs in 20 per 1000 births. Only 47% of neonates treated with the state of the art therapy (induced systemic hypothermia) have normal outcomes. Therefore, other promising therapies that potentially work in synergy with hypothermia to improve neurologic outcomes need to be tested. One potential agent is melatonin. Melatonin is a naturally occurring substance produced mainly from the pineal gland. Melatonin is widely known for its role in regulating the circadian rhythm, but it has many other effects that may benefit infants with HI injury. Melatonin serves as a free radical scavenger, decreases inflammatory cytokines, and stimulates anti-oxidant enzymes. Therefore, melatonin may interrupt several key components in the pathophysiology of HIE, in turn minimizing cell death and improving outcomes. The research study will evaluate the neuroprotective properties and appropriate dose of Melatonin to give to infants undergoing therapeutic hypothermia for hypoxic ischemic encephalopathy.

The main purpose of this study is to determine the maximum safe tolerated dose of LEV in the treatment of neonatal seizures. Our hypothesis is that optimal dosing of Levetiracetam (LEV) to treat neonatal seizures is significantly greater than 60mg/kg. This study will be an open label dose-escalation, preliminary safety and efficacy study. There will be a randomized control treatment component. Infants recognized as having neonatal seizures or as being at risk of developing seizures will be recruited and started on continuous video EEG monitoring (CEEG). Eligibility will be confirmed and consent will be obtained. In the first 2 phases of the study, neurologists will identify neonates with mild-moderate seizure burden (less than 8 minutes cumulative seizure activity per hour), appropriate for study with LEV, and exclude patients with higher seizure burden where treatment with PHB is more appropriate. Phase 3 of the dose escalation will only proceed if additional efficacy of LEV has been demonstrated in phases 1 and 2. In Phase 3 we will recruit neonates with seizures of greater severity up to 20 minute seizure burden/hour. This will make the final results of study more generalizable. If seizures are confirmed, enrolled subjects will receive 60mg/kg of LEV. Subjects whose seizures persist or recur 15 minutes after the first infusion is complete, subjects will then be randomized in the dose escalation study. Patients in the dose escalation study will be randomly assigned to receive either higher dose LEV or treatment with the control drug PHB in a 3:1 allocation ratio, stratified by site. Funding Source- FDA OOPD

NeoNOVA is a multi-site, prospective, single-arm, silent observational study to determine: among (Population) infants admitted to newborn services during their inpatient hospital stay, whether (Intervention) continuous bedside non-contact high definition video running real-time AI analysis of anatomic landmarks and movement, (Comparison) compared against human-labeled video frames and standardized clinical exams, will (Outcome) accurately localize infant anatomic landmarks (primary objective; outcome median position error in pixels) and demonstrate a statistically significant association between a video-derived movement index and clinical measures of patient neurological exams (secondary objective; outcomes N-PASS and modified Sarnat exams).

The purpose of this research study is to gather more information on how eye injury is related to a baby's future development and see if eye function and brain test results can be used, along with current measures, to better diagnose and treat babies with hypoxic-ischemic encephalopathy (HIE). Participants will undergo up to two eye exam sessions, involving both Visual Evoked Potential (VEP) and Electroretinogram (ERG) exams.

This is an observational study in patients who require clinical anesthesia. The main purpose of this study is to understand whether there are differences in the cerebral blood flow, and oxygen metabolism affected by different types of anesthesia. Subjects who require clinical anesthesia for a clinical MRI and for whom the use of anesthetics for the exam are in clinical equipoise are asked to join the study. All eligible subjects will be asked to provide informed consent before participating in the study.

This is a prospective, single center, pharmacokinetic study of intravenous hydrocortisone therapy for systemic low blood pressure during hypothermia treatment in asphyxiated newborns. Patients will be allocated to hydrocortisone supplementation while receiving conventional inotropic therapy as needed. The hypothesis is that a detailed study of hydrocortisone pharmacokinetics during therapeutic hypothermia would help to personalize steroid supplementation in asphyxiated neonates. As the overall metabolic rate decreases with lower body temperature, drug metabolism is likely to be reduced as well, and lower doses, or less frequent dosing will be sufficient to achieve the targeted steroid range and biological effects in asphyxiated neonates with relative adrenal insufficiency. Thus, the investigators are planning to measure initial, baseline serum cortisol levels and serial serum cortisol levels after hydrocortisone supplementation in cooled asphyxiated neonates.

Hypoxic-ischemic encephalopathy (HIE) affects approximately 4,000 to 12,000 persons annually in the United States. Mortality from HIE has been reported up to 60%, with at least 25% of survivors left with significant neurocognitive disability. Despite this vital unmet medical need, no pharmacological adjunct or alternative therapy has proven beneficial in improving outcomes in neonatal HIE. RLS-0071 is a novel peptide being developed for the treatment of neonatal HIE. This study is designed to evaluate the safety and tolerability of RLS-0071 in the treatment of newborns with moderate or severe HIE.

The main objective of this study is to assess pharmacokinetics features of IV sildenafil in neonates with hypoxic-ischemic encephalopathy and treated by controlled hypothermia. This phase 2 study will prepare a large phase 3 randomized controlled trial to demonstrate the superiority of a combinatory therapy associating IV sildenafil and controlled hypothermia compared to Placebo and controlled hypothermia, on survival without brain lesions on MRI at discharge, in neonates born after 36 weeks of gestation.

This observational study evaluates functional and developmental outcomes in pediatric participants undergoing a two week intensive multimodal neurorehabilitation program. The program is designed for children with neurodevelopmental disorders, including but not limited to cerebral palsy, autism spectrum disorder, developmental delay, hypoxic ischemic encephalopathy (HIE), and chromosomal or genetic abnormalities. Participants receive individualized therapy sessions for approximately 2.5 hours per day over a two week period. The intervention is not standardized but is tailored to each child's specific needs and may include components such as sensory integration, motor planning, reflex integration, oculomotor training, executive functioning activities, communication support, and other brain based therapeutic approaches. The purpose of this study is to observe changes in functional abilities, including attention, motor coordination, emotional regulation, communication, and activities of daily living. Outcomes are assessed using clinician observation and parent reported changes before and after the intensive program, with limited follow-up when available. This study does not assign participants to a specific treatment as part of a research protocol. Instead, it collects real world data from children already participating in a clinical therapy program to better understand potential benefits of intensive, individualized neurorehabilitation approaches.

Despite advances in neonatal care, moderate-to-severe acute perinatal HIE in late preterm and term infants remains a cause of mortality, neurological injury, and long-term neurodevelopmental disability. The current standard of care includes therapeutic hypothermia for 72 hours, but 40-50% of infants will die or suffer significant neurodevelopmental impairment. It has been shown that administration of hydrogen gas (H2) significantly diminishes ischemic injury in swine, and that H2 administration at the dose and duration proposed herein is well-tolerated in healthy adults. The purpose of this project is to test the feasibility and safety of H2 administration as an adjunct to therapeutic hypothermia in infants with HIE. Under exemption from informed consent, infants with severe, acute brain injury at birth will be randomized to standard therapy with or without the administration of 2% hydrogen in gases administered via the ventilator, non-invasive ventilation, or nasal cannula for 72 hours.

Sovateltide (PMZ-1620; IRL-1620) is targeted to be used as a "Treatment for hypoxic-ischemic encephalopathy in neonates," which is a life-threatening condition. Sovateltide augments neuronal progenitor cell differentiation and better mitochondrial morphology and biogenesis to activate a regenerative response in the central nervous system. The only treatment for HIE is therapeutic hypothermia with limited success, and studies indicate that sovateltide may be beneficial in these patients.

Perinatal asphyxia is a significant health problem with an incidence of 1 to 8 per 1,000 live births and can lead to serious morbidity and mortality during the neonatal period. One of its most severe consequences is hypoxic-ischemic encephalopathy (HIE), a condition that causes irreversible damage to the newborn brain due to hypoxia and ischemia. HIE is one of the leading causes of long-term neurological sequelae. Therapeutic hypothermia initiated within the first six hours after birth has been shown to significantly reduce both mortality and neurodevelopmental impairments associated with HIE. However, biomarkers that can reliably predict individual treatment response or objectively demonstrate the severity of brain injury at an early stage remain limited. Neurofilament light chain (NfL) is a protein found within the cytoskeletal structure of myelinated axons. When axonal injury occurs, NfL is released into the interstitial space and subsequently enters the cerebrospinal fluid and systemic circulation, where it can be measured. Increased NfL levels have been identified in a variety of neurological conditions, including neurodegenerative disorders and traumatic brain injury. Recent findings show that both cerebrospinal fluid and serum/plasma NfL levels are elevated in newborns diagnosed with HIE, supporting its potential role as a biochemical marker of axonal injury. The primary aim of this study is to investigate the time-dependent changes in serum NfL levels in newborns diagnosed with HIE and undergoing therapeutic hypothermia, and to evaluate the relationship between these changes, clinical findings, and neuroimaging results. For this purpose, serum NfL levels were measured at four specific time points: within the first six hours after birth (preferably cord blood), upon reaching the target cooling temperature (approximately 12-24 hours), during the rewarming phase (72-96 hours), and on the day of magnetic resonance imaging (preferably day seven). The results are expected to provide insights into the prognostic utility of NfL in HIE and contribute to determining the optimal timing for clinical sampling. The secondary objective of the study is to compare NfL levels of newborns diagnosed with HIE to those of a control group without HIE, thereby identifying potential cut-off values that may help distinguish between affected and unaffected infants.

Perinatal hypoxic-ischemic encephalopathy is a rare severe condition in which neonates present with encephalopathy and a clinical history suggestive of prenatal or perinatal hypoxic-ischemic injury. Emerging evidence suggests that genetic conditions are frequently identified in cases of perinatal HIE; however, it is unclear which neonates with this diagnosis warrant genetic testing. This study will offer clinical genome sequencing to neonates with HIE who are undergoing total body cooling (therapeutic hypothermia) and their parents.

The study aims to identify factors that predict the medium and long-term outcome of patients with disorders of consciousness (DOC) undergoing early neurological rehabilitation. In this prospective, observational study, 130 DOC patients are going to be included (36 months). At study entry, different routine data, disease severity and functional status are documented for each patient. In addition, MRI, EEG and evoked potentials are measured within the first week. The level of consciousness is recorded with the Coma-Recovery-Scale-Revised and serves as the primary outcome parameter. Complications, comorbidities, functional status and leve of consciousness are assessed weekly. After eight weeks, the measurement of the MRI, the EEG and the evoked potentials are repeated. After 3, 6 and 12 months, the Glasgow Outcome Scale-Revised is used to followed up the current status of the patients.

This research study will combine non-invasive spinal stimulation with mobility devices to examine the acute impact of the individual and combined effects of these innovative techniques on mobility in children with cerebral palsy.

The aim of this study is to determine the value of Pentoxifylline for nephroprotection in these neonates with perinatal asphyxia, using cystatin C, regional oxygenation measured near infrared spectroscopy and renal Doppler sonography.

An extension of the CORDMILK trial, the CORDMILK follow-up trial will evaluate the neurodevelopmental outcomes at 22-26 months age of term/late preterm infants who were non-vigorous at birth and received umbilical cord milking (UCM) or early cord clamping (ECC).

Study Aims Pilot study: Due to the large recruitment goal and length of the project, the study team/PIs will evaluate the first cohort of 6-10 participants to refine study procedures and study-related materials. If no major modifications are made to the protocol as a result of this evaluation, data from these participants will be included for analysis. Aim 1: Evaluate the efficacy of an early, evidence-based, clinical experience-based therapeutic intervention (from the NICU to 12-months corrected age) on improving motor function and reducing severity of motor delays in infants at 12-months corrected age. The investigators hypothesize that the intervention group will demonstrate an average 8-point difference (0.5 standard deviation) compared to the standard of care group. \[an 8-point difference is considered a clinically meaningful difference\] Aim 2: Evaluate the early effects (i.e., before 12 months) of a therapeutic intervention, provided from NICU to 12-months corrected age, on motor function and severity of motor delay. The Investigators hypothesize that a statistically significant higher percentage of infants in the intervention group will demonstrate improved motor function and reduced severity of motor delays, compared to the standard of care group-assessed using sensors, the NSMDA and TIMP-as early as 3-months corrected age. Aim 3: Evaluate whether an early intervention that focuses on caregiver engagement improves caregiver well-being. The invetigators hypothesize that an intervention that focuses on supporting and addressing the individual needs of the caregiver will improve caregiver well-being. The investigators will evaluate these effects using the PedsQL (Family Impact Module).

The overall aim of the study is to evaluate the prevalence of motor- and neurological disorders (cerebral pares and other less severe motor disorders) in Swedish infants with a high-risk neonatal period and to elucidate whether these children receive motor related health care (MRHC) at 2 and or 5,5 years of age.

Ammonia is a waste product of protein and amino acid catabolism and is also a potent neurotoxin. High blood ammonia levels on the brain can manifest as cytotoxic brain edema and vascular compromise leading to intellectual and developmental disabilities. The following aims are proposed: Aim 1 of this study will be to determine the chronology of biomarkers of brain injury in response to a hyperammonemic (HA) brain insult in patients with an inherited hyperammonemic disorder. Aim 2 will be to determine if S100B, NSE, and UCHL1 are altered in patients with two other inborn errors of metabolism, Maple Syrup Urine Disease (MSUD) and Glutaric Acidemia (GA1).

This will be a five year study that will be a prospective, randomized, controlled trial (RCT) to assess the effect of a virtual early intervention care delivery model in the provision of therapy to enhance the neurodevelopmental trajectory of infants with brain injury. In addition, the investigators will enhance understanding of the social and parental contributors to outcomes and the early health economic impact of a virtual clinic. The results of this study will help inform the design of a larger, multi-center randomized controlled trial.