Clinical Research Directory

Outcomes of Early Versus Late Tracheostomy in Critically Ill Patients Due to Head Injury: A Randomized Controlled Trial

Tracheostomy is a surgical procedure that involves creating an opening in the trachea and bringing it to the skin surface to form a stoma. It may be performed as an emergency or elective operation. The main indications include relief of upper airway obstruction, protection of the lower respiratory tract, and facilitation of assisted ventilation in critically ill patients. Further studies are needed to identify the patient populations that may benefit from early tracheostomy. Therefore, this study was conducted to evaluate early tracheostomy (≤7 days) compared with late tracheostomy (\>7 days) in relation to the occurrence of ventilator-associated pneumonia, duration of mechanical ventilation, length of hospital stay, and 30-day mortality in critically ill patients with traumatic head injury.

Control Network Neuromodulation to Enhance Cognitive Training in Complex Traumatic Brain Injury

The CONNECT-TBI Trial aims to develop safe, effective treatments for complex mTBI that improve cognitive functioning. Based on the compelling preliminary data generated by our study team, the objective of this study is to conduct a randomized, double-blinded, sham-controlled Phase II clinical trial of APT-3 combined with rTMS, HD-tDCS, or sham to treat cognitive control deficits in Veterans with complex mTBI and PPCS. At the Baseline Visit, participants will undergo demographic, neuropsychological, behavioral, and quality of life testing. They will also undergo structural MRI to permit modeling of their brain, resting/task-related fMRI to identify the CCN, and pseudocontinuous arterial spin labeling (pCASL) and diffusion tensor imaging (DTI) to assess for other pathologies. They will then be randomized to 16 sessions of APT-3 with concurrent rTMS, HD-tDCS, or sham stimulation delivered to the unique functional left dorsolateral prefrontal cortex (DLPFC), a primary node of the CCN. Lastly, they will repeat all baseline tests, and report on 3- and 6-month recovery levels to establish longevity and stability of subjective benefit. Given that this individualization protocol has never been attempted for cognitive rehabilitation in military mTBI, we expect this trial will generate useful effect sizes for HD-tDCS and rTMS to be used for powering the next step, a Phase III multi-center trial.

hCG Treatment for Rehabilitation From a TBI

The COGNI-REHAB Trial is a single-site, phase O/I, randomized, double-blind, placebo-controlled study of human chorionic gonadotropin (hCG; choriogonadotropin alfa, Ovidrel®) in men with post-acute, moderate to severe traumatic brain injury (msTBI). Its objective is to assess the safety and efficacy of a 24-week regimen of Ovidrel (125 micrograms twice weekly) compared to placebo on treatment-emergent adverse events (TEAEs), cognitive and functional recovery, and circulating sex hormones.

Evaluation and Diagnosis of Potential Research Subjects With Traumatic Brain Injury

Background: \- The Center for Neuroscience and Regenerative Medicine is working to improve physicians' understanding of brain injury. More information is needed on traumatic brain injury (TBI), especially how well a person recovers from TBI and how the brain changes over time in people with TBI. To conduct this research, the center is sponsoring a number of research studies on TBI and is interested in evaluating individuals with TBI or post-concussive syndrome to determine if they might be eligible for future studies. Objectives: \- To develop a pool of individuals with traumatic brain injury and post-concussive syndrome for future research studies. Eligibility: \- Individuals at least 18 years of age who have symptoms of or have been diagnosed with traumatic brain injury or post-concussive syndrome and are willing to participate in future studies. Design: * Participants will be screened with an initial telephone interview, and will be asked to come to the National Institutes of Health for an in-person screening visit. * At the screening visit, participants will provide a medical history, have a physical examination and complete a study questionnaire on their TBI and its symptoms, including how the injury occurred, when it occurred, and any previous brain-related injuries. * Subjects may also return for a second visit at the NIH CC if eligible. * Each visit may involve blood samples, an MRI scan, and a series of tests to evaluate brain function. * Participants will also provide contact information to enable researchers to contact them for future studies.

Deployment of a Novel National Institute of Neurological Disorders and Stroke Clinical, Biomarker, Imaging, and Modifiers (CBI-M) Classification Framework for Emergency Department Patients With Glasgow Coma Scale 15 Traumatic Brain Injury (PIONEER-Prognosis)

This study is being done to learn how information from blood tests, medical records, and wearable devices that track sleep, activity, and heart rate can help predict how people recover after a concussion. The goal is to improve how doctors monitor recovery and give patients better information about what to expect after a head injury.

Sovateltide for the Treatment of Acute Traumatic Brain Injury

Traumatic brain injury (TBI) remains a leading cause of global disability, yet current clinical management is limited to supportive care and pressure stabilization using hyperosmolar therapies like mannitol and hypertonic saline. These strategies fail to address the destructive cellular cascades that persist long after the initial impact, leaving 66.3% of severe TBI patients with permanent cognitive and neurological deficits. To bridge this critical unmet medical need, the therapeutic focus must shift toward neuroprotective and neuroregenerative agents that actively block secondary injury cascades such as excitotoxicity, apoptosis, and chronic neuroinflammation. Sovateltide is a selective endothelin-B receptor agonist. It was previously reported to reduce apoptosis, stimulate neurogenesis, and improve functional recovery. Unlike most TBI candidates restricted to preclinical phases, sovateltide possesses a robust human safety and tolerability profile established across Phase I, II, III, and IV ischemic stroke trials. We conducted a preclinical study in Wistar rats with induced TBI and showed that sovateltide effectively preserved BBB integrity, a critical determinant of post-injury outcomes, and significantly reduced neuronal apoptosis, as evidenced by decreased expression of caspase-3 and caspase-6, key markers of programmed cell death. Treated animals also exhibited notable improvements in neurobehavioral performance, reflecting functional recovery likely attributable to the drug's antioxidant, anti-inflammatory, and anti-apoptotic mechanisms. These results align with earlier evidence showing that ETB receptor activation enhances angiogenesis, neurogenesis, and synaptic remodeling, processes essential for neural repair following brain injury. The present study has been designed to advance sovateltide (IRL-1620) into a pivotal Phase III clinical trial for acute traumatic brain injury (TBI). With millions affected annually and zero approved neuroprotective pharmacotherapies available, this milestone marks a critical step forward in addressing one of modern medicine's greatest unmet needs. By harnessing our proprietary neural repair discovery platform, sovateltide targets the cascade of secondary cell death while stimulating neurogenesis and angiogenesis. Building on the strong momentum of our ongoing global Phase III RESPECT-ETB study in acute ischemic stroke, this study will further validate the broad therapeutic potential of our endothelin-B receptor platform across severe acute neurovascular conditions.

Music Therapy for Comatose Brain Injured Patients

The goal of this single-arm observational study is to determine whether alpha music therapy, initiated early in the recovery period, can improve cognitive function for severe traumatic brain injury patients when compared to historic controls. Participants will listen to selected music through headphones. The investigators will compare cognitive function between groups at three time points: ICU discharge, hospital discharge, and three months after injury.

Memantine Targeting Neurovascular Dysfunction After Mild and Moderate Traumatic Brain Injury (MEND)

The goal of this pilot clinical trial is to learn whether memantine can be given safely and successfully to adults in hospital with a mild or moderate traumatic brain injury (TBI). Memantine is approved to treat Alzheimer's disease, but it is not approved to treat TBI. The study will also test whether brain scans and other assessments are suitable for a larger trial. TBI can damage the blood-brain barrier. This protective lining controls what can pass from the bloodstream into the brain. Researchers can measure this damage with a specialized magnetic resonance imaging (MRI) scan using contrast dye. The main questions are: * Can participants start memantine soon after their injury and take it for three months? * How safe and tolerable are daily memantine doses of 20 mg and 30 mg? * Can MRI scans measure changes in the blood-brain barrier from the start of the study to three months? * Can researchers complete the study visits and collect enough information to plan a larger trial? The study will include 45 adults admitted to the Halifax Infirmary in Nova Scotia, Canada, with a non-penetrating mild or moderate TBI. A computer will assign each participant by chance to one of three groups. One group will receive 20 mg of memantine per day. Another group will receive 30 mg per day. The third group will receive usual care without memantine. The memantine dose will increase gradually based on how well each participant tolerates it. Participants will: * Receive usual care, with or without memantine for three months; * Have specialized MRI scans near the start of the study and at three months; * Have recordings of brain activity near the start, at three months, and at six months; and * Complete tests and questionnaires about symptoms, memory, attention, mood, daily function, disability, and quality of life. Researchers will compare the groups to look for differences in blood-brain barrier changes, side effects, and recovery measures. Because this is a small pilot study, it is not designed to prove that memantine improves recovery. Its results will instead help researchers choose a dose, assess safety of drug delivery, and design a larger trial.

Effect of Aerobic Exercise Training on Cardiorespiratory Function in Patients With Traumatic Brain Injury

Background: \- Many people who have traumatic brain injury (TBI) have low levels of physical fitness. Low physical fitness causes severe fatigue that reduces the ability to perform routine daily activities, and may also cause increased depression, anxiety, or sadness. Aerobic exercise, such as treadmill walking or running, improves physical fitness in most people and may also decrease fatigue and improve mood. However, more information is needed to determine if exercise improves these conditions in people who have TBI. Objectives: \- To examine the effect of an aerobic treadmill walking exercise program on physical fitness, fatigue, and mood in people with TBI. Eligibility: \- Individuals between 21 and 45 years of age who had a nonpenetrating traumatic brain injury at least 6 months before participating; able to understand oral and written English language, give informed consent and sign a consent form; are physically inactive (including activities related to both job and recreation); and are able to stand and walk on a treadmill safely without help. Design: * This study requires 4 testing visits and 36 exercise visits over 14 weeks. * The first and third testing visits will last about 4 hours and the second and final testing visits will take about 2 hours. * Testing visits will consist of a medical history and physical examination, completion of questionnaires (about fatigue, daily physical activity, sleep quality, mood, and overall quality of life), tests of thinking and a treadmill exercise test. * Participants will have treadmill exercise training 3 days per week for 12 weeks. Each session includes a check-in, warm-up, treadmill walking at the training heart rate, and cool-down. Thirty-two of the sessions will last for about 1 hour, and four of the sessions will include questionnaires to fill out and will last about one-and-a-half hours. * After completing the exercise training program, participants will have a final testing visit to complete the questionnaires (about fatigue, daily physical activity, sleep quality, mood, and overall quality of life), tests of thinking and a treadmill exercise test.

Feasibility and Outcomes of 3D-printed External Cranial Orthosis After Craniectomy

This study will compare the outcomes of a current clinical implementation of PEACO designed for one-handed donning and doffing with carer-monitoring with a previous prototype (HPPD) requiring carer-donning and doffing with therapist monitoring.

Effects of Rapid-Resisted Exercise and Bright Light Therapy on Ambulatory Adults With Traumatic Brain Injury

Background: * Traumatic brain injury may have a range of effects, from severe and permanent disability to more subtle functional and cognitive deficits that often go undetected during initial treatment. To improve treatments and therapies and to provide a uniform quality of care, more research is needed into different treatments for traumatic brain injury. * Exercise has been shown to improve movement and balance in people with strokes, cerebral palsy, and other conditions that affect the brain, and can improve symptoms of memory problems or depression. Bright light therapy has also been shown to improve mood in people with depression. Researchers are interested in studying problems with movement, balance, thinking, and mood in people with traumatic brain injury. By comparing the effects of exercise and bright light exposure on brain function, new treatments may be developed for acute traumatic brain injury. Objectives: \- To compare the effects of exercise and bright light therapy on the brain function of individuals with traumatic brain injury. Eligibility: \- Individuals between 18 and 44 years of age who either have been diagnosed with traumatic brain injury or are healthy volunteers. Design: * Individuals with traumatic brain injury will have four outpatient evaluation visits at the clinical center, a 3-month home exercise program, and a 3-month bright light exposure program at home. Healthy volunteers will have one evaluation visit at the clinical center. * At the first study visit, all participants will have a full physical examination and medical history. Individuals with traumatic brain injury will also have an eye exam to determine if it is safe for them to receive light therapy. * All participants will have the following initial tests: * Tests of walking and movement, including monitoring by a physical therapist; tests to record joint movement and evaluate muscle function; tests that combine movement, thinking, and speaking; and balance and reaction time tests. * Magnetic resonance imaging scans * Tests of thinking and mood, including questionnaires, computerized tests, and simple action tests. * Participants with traumatic brain injury will have separate 3-month sessions of exercise and bright light therapy, with additional evaluation visits between each 3-month session and at the end of the study. Between the 3-month sessions, participants will have 1 month with no intervention. * Exercise sessions will involve regular workouts on an elliptical machine for 30 minutes for 5 days a week, and bright light therapy sessions will involve sitting in front of a light box for 30 minutes for 5 days a week. Participants will keep a journal to monitor the effects of the therapy.

Narrative Discourse Treatment Development

Discourse impairments are breakdowns in meaningful communication beyond the level of single sentences and have a functional impact on the lives of Veterans with traumatic brain injury (TBI), disrupting return to work, communication re integration, socialization, and quality of life. The few prior attempts to treat discourse impairments have been small case studies and resulted in no change or limited gains. The proposed study evaluates the feasibility of a novel narrative discourse treatment that builds upon these prior attempts by addressing breakdowns in both story content and story organization using a theoretically-driven approach. If feasible, as demonstrated by tolerability and acceptability to participants, and later shown to be effective, the proposed discourse treatment has the potential to improve daily communication, which provides a gateway for Veterans with TBI to increase meaningful participation and improve functioning in major life domains.

Machine Learning to Predict Factors Affecting Rehabilitation Length of Stay and Healthcare Costs for Neurological Rehabilitation

The aim of this retrospective study is to ascertain total direct costs, rehabilitation length of stay (RLOS) and factors associated with RLOS for neurological inpatient rehabilitation at the tertiary care hospital.

Ketamine in Severe Traumatic Brain Injury

Traumatic brain injury (TBI) accounts for approximately 2.5 million visits to emergency departments in the United States each year. After decades of research, management strategies for severe TBI (sTBI) patients are still evolving. Optimizing intracranial pressure (ICP) and cerebral perfusion pressure (CPP) are paramount in the management of these patients and placement of these monitors is the current standard-of-care. However, monitoring brain oxygenation (PbtO2) with invasive intraparenchymal monitors is currently under investigation in the management of severe TBI and placement of these monitors is gaining widespread use. This has opened the door for the use of tiered therapy to optimize ICP and PbtO2 simultaneously. Current evidence indicates that correction of ICP, CPP and PbtO2 in sTBI requires optimized analgesia and sedation. Ketamine is one of the few drugs available that has both sedative and analgesic properties and does not commonly compromise respiratory drive like opioids and sedative-hypnotics. However, traditionally, ketamine has been viewed as contraindicated in the setting of TBI due to concerns for elevation in ICP. Yet, new data has cast this long-held assumption into significant doubt. Hence the present pilot study will characterize the neurophysiological response to a single dose of ketamine in critically-ill TBI patient with ICP and PbtO2 monitoring.

Carbon Dioxide Administration and Brain Waste Clearance

The current study tests whether different exposures to carbon dioxide (CO2) can safely result in the increased movement of proteins from the brain into the blood. The investigators believe that this would be a proxy for the brain clearing waste products more effectively. The current study will use a counter-balanced design, in which individuals with and without a history of traumatic brain injury (TBI) will receive different levels of CO2 (targeted changes of approximately 5 or 10 mmHG in end-tidal CO2) approximately one week apart. The counter-balanced design means that each participant receives a single dose of CO2 at each visit, and different doses of CO2 at each visit. The order in which participants receive the dose is randomized, and the participant will not be informed of the dose.

Modulating Inflammation in Neuro-Trauma

MINT is a single-site, prospective, randomized, double-blind, sham-controlled pilot trial evaluating the safety and feasibility of transcutaneous auricular vagus nerve stimulation (taVNS) in patients with moderate to severe traumatic brain injury (GCS 3-12). Participants will be randomized to receive either active taVNS or sham stimulation using the same device. The primary objective is to assess the safety and feasibility of taVNS implementation in the acute TBI setting. Secondary objectives include exploratory measurement of serum inflammatory and neuronal injury biomarkers and assessment of functional outcome using the Extended Glasgow Outcome Scale at hospital discharge.

Targeting Osteosarcopaenia and Multimorbidity for Frailty Prevention

The aging population and its accompanying burden from non-communicable chronic diseases predicts an increasing impact imposed by frailty on healthcare systems. This is due to a lack of normative data for older adults and reliable risk stratification methods to develop effective approaches to the prevention of frailty. In this study, the investigators plan to form a common dataset for phenotype identification, risk stratification of frailty and its targeted treatment plans in the at-risk and mildly frail population.

Evaluation, Pathogenesis, and Outcome of Subjects With or Suspected Traumatic Brain Injury

Background: \- Traumatic brain injury may have a range of effects, from severe and permanent disability to more subtle functional and cognitive deficits that often go undetected during initial treatment. To improve treatments and therapies and to provide a uniform quality of care, researchers are interested in developing more standardized criteria for diagnosing and classifying different types of traumatic brain injury. By identifying imaging and other indicators immediately after the injury and during the initial treatment phrase, researchers hope to better understand the nature and effects of acute traumatic brain injury. Objectives: * To study the MRI results of individuals who have recently had head injury and suspected traumatic brain injury. * To study the natural evolution of traumatic brain injury for up to 3 months after head injury. Eligibility: \- Individuals at least 18 years of age who have been admitted to a hospital with a diagnosed or suspected traumatic brain injury within the past 48 hours. Design: * Participants will have one 3-hour study visits: an initial visit (within 48 hours of head injury). Participants may be asked to have an optional 4-day, 30-day, 90-day, and 1-year follow-up. * Each visit may involve blood samples, an MRI scan (approximately 30 minutes), and a series of tests to evaluate brain function. * At the optional follow-up visit, participants may have blood samples, an MRI scan, and a general traumatic brain injury assessment. * This study does not provide treatment and does not replace any current therapies. However, participants who are eligible for other National Institutes of Health studies may be referred to these studies by researchers.

Invasive Versus Non-Invasive Intracranial Pressure-Guided Management in Neurosurgical Patients

Raised intracranial pressure (pressure inside the skull) is a serious complication for patients with brain injuries, strokes, or tumors. Managing this pressure is critical to prevent further brain damage. This study compares two different methods of monitoring and managing brain pressure to see which leads to better patient recovery. Participants in this study are adult patients admitted to the neurosurgery department who require monitoring for high brain pressure. The study involves two groups: 1. Invasive Monitoring Group: Patients receive a standard treatment where a small tube (external ventricular drain) is surgically placed into the fluid spaces of the brain to directly measure pressure and drain fluid if needed. 2. Non-Invasive Monitoring Group: Patients are monitored using an ultrasound on the outside of the eye to measure the swelling of the optic nerve, which estimates brain pressure without requiring surgery. The main goal of this study is to compare how patients in each group recover by tracking their level of consciousness (using the Glasgow Coma Scale) over their first five days of admission. The study will also evaluate patient recovery at the time of hospital discharge, the length of the hospital stay, and any medical complications.

Evaluation of the SCALED (SCaling AcceptabLE cDs)

This project will adapt a currently deployed Clinical Decision Support (CDS) system to deliver a VTE prevention guideline for adult patients with traumatic brain injury (TBI). We believe this is an ideal PCOR use case given PCORI's continued effort to combat VTE in trauma and our experience previously implementing this guideline. The Our overall goal is to successfully scale, evaluate, and maintain an interoperable TBI CDS across 7 total institutions.

Effectiveness of Music Therapy on Level of Consciousness

It is known that even in patients with severe disorders of consciousness (DOC), the perception of known stimuli triggers emotional reactions that can be interpreted as an expression of a residual function of consciousness. Music therapy has a long tradition in neurological rehabilitation. Frequently, active therapies with own music making and singing are implemented in clinical settings. In DOC patients, it is more likely to use passive music listening. However, findings on effectiveness are limited, as only a few studies have systematically investigated the effects of music therapy in this population. Therefore, the investigators want to investigate the effectiveness of passive listening to preferred music on the level of consciousness.

Prognostic Factors to Regain Consciousness

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.

Reliability and Validity of the PReFS

This study is testing the psychometric properties of a new tool to determine recommendations for pressure relief frequency in wheelchair users.

CoMind Early Feasibility Study

The purpose of this research, which has been determined as non-significant risk by the central IRB overseeing the study, is to obtain information to help further develop a machine (a medical device) to measure the pressure around the brain from the outside (this pressure is called intracranial pressure or ICP). Monitoring and managing ICP is an important part of care for patients with conditions such as Traumatic Brain Injury (TBI). However, the current way of measuring ICP requires surgery to drill a hole into the skull, and therefore can introduce additional risks such as infections and pain. Recent research has shown it may be possible to measure ICP without needing surgery. This technology is in development, but large amounts of data is required to build these new devices. Through collecting a large database of information from patients who have both the routine surgical device and the research device applied to their head, the research team will work to develop and test an effective and potentially safer way of monitoring patient ICP.