Clinical Trials in the Spotlight

The purpose of this study is to evaluate the role of single dose 4-aminopyridine (4-AP) on the diagnosis of severing vs non-severing nerve injury after peripheral nerve traction and/or crush injury. The investigational treatment will be used to test the hypothesis that 4-aminopyridine can speed the determination of nerve continuity after peripheral nerve traction and/or crush injuries allowing the identification of incomplete injuries earlier than standard electrodiagnostic (EDX) and clinical assessment. Participants will be randomized to one of two groups to determine the order of treatment they receive (drug and placebo vs placebo and drug). Participants will undergo baseline testing for nerve assessment, receive either drug or placebo based on randomization and undergo hourly sensory and motor evaluation, EDX testing and serum 4AP levels for three hours after dosing. Participants will then repeat this with the crossover arm.

This is a phase III trial to determine whether adjunctive sertraline will lead to improved survival 18-week survival. There was an initial phase I/II unmasked dose finding pharmacokinetic study of CSF concentrations in 172 persons conducted from August 2013 to August 2014. See NCT03002012.

Primary Aim: To determine if apixaban is superior to aspirin for prevention of the composite outcome of any stroke (hemorrhagic or ischemic) or death from any cause in patients with recent ICH and atrial fibrillation (AF). Secondary Aim: To determine if apixaban, compared with aspirin, results in better functional outcomes as measured by the modified Rankin Scale.

ENCHANTED is an independent, investigator initiated, international collaborative, quasi-factorial randomised controlled trial involving a package of 2 linked comparative randomised treatment arms, which aims to address 4 key questions in patients eligible for thrombolysis in the acute phase of ischaemic stroke. (1) Does low-dose (0.6 mg/kg) intravenous (i.v.) recombinant tissue plasminogen activator (rtPA) provide equivalent benefits compared to standard-dose (0.9 mg/kg) rtPA? (2) Does intensive blood pressure (BP) lowering (130-140 mmHg systolic target) improve outcomes compared to the current guideline recommended level of BP control (180 mmHg systolic target)? (3) Does low-dose (0.6 mg/kg) intravenous (i.v.) recombinant tissue plasminogen activator (rtPA) reduce the risk of symptomatic intracerebral haemorrhage (sICH)? (4) Does the addition of intensive BP lowering to thrombolysis with rtPA reduce the risk of any intracerebral haemorrhage (ICH)? The rtPA dose arm of the study addressing questions (1) and (3) concluded with a publication of the results in May 2016. The BP intensity arm of the study addressing questions (2) and (4) concluded with a publication of the results in February 2019.

The primary objective is to determine the most effective and/or the least effective treatment of benzodiazepine-refractory status epilepticus (SE) among patients older than 2 years. There are three active treatment arms being compared: fosphenytoin (FOS),levetiracetam (LEV), and valproic acid (VPA). The second objective is comparison of three drugs with respect to secondary outcomes. The final objective is to ensure that the trial is informative for treatment of established SE in children by describing the effectiveness, safety, and rate of adverse reactions of these drugs in children.

Objective: This protocol is designed to allow evaluation of participants neurosurgical disorders that receive care within the Surgical Neurology Branch. The participants will receive standard-of-clinical-care evaluation and treatment. The clinical data and samples generated during standard of care treatment will be collected as a part of this study. Study Population: Participants 4 years of age and older with neurosurgical-related conditions seeking care from, or referred to the Surgical Neurology Branch for evaluation are eligible for this protocol. Study Design: This is an observational study. Participants will receive standard-of- clinical-care evaluation and treatment for their neurosurgical condition. Clinical evaluation may include laboratory and radiological studies designed to aid in diagnosis or differential diagnosis of the participant s condition or to facilitate treatment. The evaluations may take place in the outpatient clinic areas or in the inpatient units. Some participants will receive standard-of-care medical or surgical treatment for their disorder. Clinical data, tissue samples or body fluids obtained during standard of care treatment, may be used for research. Additional genetic testing may be performed on subjects and their blood relatives if a genetic mechanism underlying the neurological disorder is suspected. Patients in this study may choose to consent to skin biopsies for research purposes, in which case they will sign an additional consent document for thesethis research procedure. Outcome Measures: No additional research outcome measures will be tracked in this study, as this study is collecting data for potential future use. All outcomes will be those of standard clinical evaluation and treatment. A clinical and research database will be kept of patient s diagnosis, progression, and treatment. Clinical database information may be reported or be used in other studies.

Fibrinogen replacement could prevent haemorrhagic complications in ischemic stroke patients with secondary post-rtPA hypofibrinogenemia

The objectives of the proposed research among this population are: 1) to define clinically meaningful change (i.e. differentiating states of health and illness) with respect to urinary symptoms, urine inflammation, cultivable bacteria, and the urine ecosystem; and 2) to determine the optimal intravesical Lactobacillus RhamnosusGG (LGG®) dose to be used to reduce urinary symptoms in a future clinical trial.

The objectives of the proposed research among this population are: 1) to define clinically meaningful change (i.e. differentiating states of health and illness) with respect to urinary symptoms, urine inflammation, cultivable bacteria, and the urine ecosystem; and 2) to determine the optimal intravesical Lactobacillus RhamnosusGG (LGG®) dose to be used to reduce urinary symptoms in a future clinical trial.

This is the first ever comparative effectiveness study of an antibiotic-sparing novel self-management intervention to prevent complicated urinary tract infection (UTI).

This is a mechanistic randomized controlled trial of 134 patients with lower extremity chronic neuropathic pain randomized to stable conventional medical management (CMM) or combined CMM and peripheral nerve stimulation therapy (PNS+CMM). All participants will undergo baseline and monthly remote assessments for up to 1 year. Quantitative sensory testing (QST) will be performed in all participants at baseline, 30 days, and 3 months, with an additional QST session in PNS implanted patients at 6 months. The local expression of sigma-1 receptors in chronic pain allows for visualization of peripheral pain generators, and the investigators will utilize a novel PET radiotracer highly selective for the sigma-1 receptor correlating with local receptor density and pain symptoms. 78 patients (39 in each arm, only at Stanford) will undergo \[18F\]FTC-146 PET/ MRI at baseline. 5 patients will also receive PET/CT of the lower extremities at baseline. These 78 patients will also receive \[18F\]FTC-146 PET/CT at 3 months. The investigators will characterize treatment interactions with participant attributes and baseline QST pain sensitivity measures in predicting treatment response; examine depression and physical function as mediators of treatment response; compare longitudinal pain, depressive symptom, pain catastrophizing, physical function, and QST trajectories across treatments, compare acute QST responses to PNS after stable implantation, and determine whether peripheral imaging markers correlate with baseline pain and treatment response.

The primary efficacy objective of the MOST trial is to determine if argatroban (100µg/kg bolus followed by 3µg/kg per minute for 12 hours) or eptifibatide (135µg/kg bolus followed by 0.75µg/kg/min infusion for two hours) results in improved 90-day modified Rankin scores (mRS) as compared with placebo in acute ischemic stroke (AIS) patients treated with standard of care thrombolysis (0.9mg/kg IV rt-PA or 0.25mg/kg IV tenecteplase or TNK) within three hours of symptom onset. Patients may also receive endovascular thrombectomy (ET) per usual care. Time of onset is defined as the last time the patient was last known to be well.

The objective of the rFVIIa for Acute Hemorrhagic Stroke Administered at Earliest Time (FASTEST) Trial is to establish the first treatment for acute spontaneous intracerebral hemorrhage (ICH) within a time window and subgroup of patients that is most likely to benefit. The central hypothesis is that rFVIIa, administered within 120 minutes from stroke onset with an identified subgroup of patients most likely to benefit, will improve outcomes at 180 days as measured by the Modified Rankin Score (mRS) and decrease ongoing bleeding as compared to standard therapy.

The SATURN trial aims to determine whether continuation vs. discontinuation of statin drugs after spontaneous lobar intracerebral hemorrhage (ICH) is the best strategy; and whether the decision to continue/discontinue statins should be influenced by an individual's Apolipoprotein-E (APOE) genotype. An MRI ancillary study (SATURN MRI), in a subset of SATURN participants , will evaluate the effects of continuation vs. discontinuation of statin drugs on hemorrhagic and ischemic MRI markers of cerebral small vessel disease, and whether the presence/burden of hemorrhagic markers (i.e. cerebral microbleeds and/or cortical superficial siderosis) on baseline MRI influences the risk of ICH recurrence on/off statin therapy.

Study Population: Subjects with Mild Acute Ischemic Stroke in the anterior circulation within 24 hours from onset. Study objectives: 1. Identify the personal stimulation level for each patient based on physiological biomarkers 2. Identify improvement in stroke symptoms during ISS treatment at the personal stimulation level

Pain is common in children presenting to the emergency department but is frequently undertreated, leading to both short- and long-term consequences. Morphine is the standard treatment for children with moderate to severe acute pain, but its use is associated with serious side effects and caregiver and clinician concerns related to opioid administration. The investigators aim to determine if sub-dissociative ketamine is non-inferior to morphine for treating acute pain and a preferable alternative for treating acute pain in children because of its more favorable side effect profile and potential long-term benefits related to pain-related function, analgesic use/misuse, and mental and behavioral health outcomes.

Background: - Deep brain stimulation (DBS) is an approved surgery for certain movement disorders, like Parkinson's disease, that do not respond well to other treatments. DBS uses a battery-powered device called a neurostimulator (like a pacemaker) that is placed under the skin in the chest. It is used to stimulate the areas of the brain that affect movement. Stimulating these areas helps to block the nerve signals that cause abnormal movements. Researchers also want to record the brain function of people with movement disorders during the surgery. Objectives: - To study how DBS surgery affects Parkinson s disease, dystonia, and tremor. - To obtain information on brain and nerve cell function during DBS surgery. Eligibility: - People at least 18 years of age who have movement disorders, like Parkinson's disease, essential tremor, and dystonia. Design: - Researchers will screen patients with physical and neurological exams to decide whether they can have the surgery. Patients will also have a medical history, blood tests, imaging studies, and other tests. Before the surgery, participants will practice movement and memory tests. - During surgery, the stimulator will be placed to provide the right amount of stimulation for the brain. Patients will perform the movement and memory tests that they practiced earlier. - After surgery, participants will recover in the hospital. They will have a followup visit within 4 weeks to turn on and adjust the stimulator. The stimulator has to be programmed and adjusted over weeks to months to find the best settings. - Participants will return for followup visits at 1, 2, and 3 months after surgery. Researchers will test their movement, memory, and general quality of life. Each visit will last about 2 hours.

Background: - Medically intractable epilepsy is the term used to describe epilepsy that cannot be controlled by medication. Many people whose seizures do not respond to medication will respond to surgical treatment, relieving seizures completely or almost completely in one-half to two-thirds of patients who qualify for surgery. The tests and surgery performed as part of this treatment are not experimental, but researchers are interested in training more neurologists and neurosurgeons in epilepsy surgery and care in order to better understand epilepsy and its treatment. Objectives: - To use surgery as a treatment for medically intractable epilepsy in children and adults. Eligibility: - Children and adults at least 8 years of age who have simple or complex partial seizures (seizures that come from one area of the brain) that have not responded to medication, and who are willing to have brain surgery to treat their medically intractable epilepsy. Design: - Participants will be screened with a medical history, physical examination, and neurological examination. Imaging studies, including magnetic resonance imaging and computer-assisted tomography (CT), may also be conducted as part of the screening. Participants who do not need surgery or whose epilepsy cannot be treated surgically will follow up with a primary care physician or neurologist and will not need to return to the National Institutes of Health for this study. - Prior to the surgery, participants will have the following procedures to provide information on the correct surgical approach. - Video electroencephalography monitoring to measure brain activity during normal activities within a 24-hour period. Three to four 15-minute breaks are allowed within this period. - Wada test to evaluate speech, comprehension, and memory centers of the brain, using a contrast dye to study the blood vessels of the brain and a short-term anesthetic administration procedure to test the effects on areas of speech and memory. - Depth electrodes and/or brain surface electrodes to measure brain activities and determine the part of the brain that is responsible for the seizures (seizure focus). - Participants will have a surgical procedure at the site of their seizure focus. Brain lesions, abnormal blood vessels, tumors, infections, or other areas of brain abnormality will be either removed or treated in a way that will stop or help prevent the spread of seizures without affecting irreplaceable brain functions, such as the ability to speak, understand, move, feel, or see. - Participants will return for outpatient visits and brain imaging studies 2 months, 1 year, and 2 years after surgery.

Background: Some people with brain tumors have seizures related to the tumor. This is called tumor-related epilepsy. Usually brain tumors are treated by removing as much of the brain tumor as possible without causing problems. Researchers think this may improve the outcome for people with brain tumors. It may completely relieve or greatly reduce the number of seizures they have. Objectives: To evaluate people with brain tumors that are associated with seizures and to offer surgical treatment. Also, to study how surgery affects seizures. Eligibility: People age 8 and older who have a brain tumor with associated seizures. They must be willing to have brain surgery to treat their epilepsy. Design: Participants will be screened with a review of their medical records. Participants will have a medical history and physical exam. Participants will be admitted to the hospital at NIH. They will have Medical history Physical exam Neurological exam Tests of memory, attention, and thinking Questions about their symptoms and quality of life Blood drawn They may also have: MRI or CT scan. They will lie on a table that slides in and out of a machine that takes pictures. For part of the MRI, they will get a dye through an intravenous (IV) catheter. Video electroencephalography monitoring. Electrodes will be placed on the scalp. The participant s brain waves will be recorded while doing normal activities. Participants will be videotaped. Participants will keep a seizure diary before and after surgery. Participants will have surgery to remove their brain tumor and the brain area where their seizures start. They will stay in the hospital up to a week after surgery. Participants have for follow-up visits at NIH.

Background: - Deep brain stimulation (DBS) is an approved surgery for certain movement disorders, like Parkinson's disease, that do not respond well to other treatments. DBS uses a battery-powered device called a neurostimulator (like a pacemaker) that is placed under the skin in the chest. It is used to stimulate the areas of the brain that affect movement. Stimulating these areas helps to block the nerve signals that cause abnormal movements. Researchers also want to record the brain function of people with movement disorders during the surgery. Objectives: - To study how DBS surgery affects Parkinson s disease, dystonia, and tremor. - To obtain information on brain and nerve cell function during DBS surgery. Eligibility: - People at least 18 years of age who have movement disorders, like Parkinson's disease, essential tremor, and dystonia. Design: - Researchers will screen patients with physical and neurological exams to decide whether they can have the surgery. Patients will also have a medical history, blood tests, imaging studies, and other tests. Before the surgery, participants will practice movement and memory tests. - During surgery, the stimulator will be placed to provide the right amount of stimulation for the brain. Patients will perform the movement and memory tests that they practiced earlier. - After surgery, participants will recover in the hospital. They will have a followup visit within 4 weeks to turn on and adjust the stimulator. The stimulator has to be programmed and adjusted over weeks to months to find the best settings. - Participants will return for followup visits at 1, 2, and 3 months after surgery. Researchers will test their movement, memory, and general quality of life. Each visit will last about 2 hours.