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HOUSE JOINT RESOLUTION NO. 561
Commending Paul Berger
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 Paul Named Virginia Advocate of the Year
AHA's "You're the Cure" Honor
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Stephanie receives Fairfax Caregiver
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Stephanie blogs for Disruptive Women in Healthcare

What Research is Being Done by the NINDS?

The NINDS is the leading supporter of stroke research in the United States and sponsors a wide range of experimental research studies, from investigations of basic biological mechanisms to studies with animal models and clinical trials.

Currently, NINDS researchers are studying the mechanisms of stroke risk factors and the process of brain damage that results from stroke. Some of this brain damage may be secondary to the initial death of brain cells caused by the lack of blood flow to the brain tissue. This secondary wave of brain injury is a result of a toxic reaction to the primary damage and mainly involves the excitatory neurochemical, glutamate. Glutamate in the normal brain functions as a chemical messenger between brain cells, allowing them to communicate. But an excess amount of glutamate in the brain causes too much activity and brain cells quickly "burn out" from too much excitement, releasing more toxic chemicals, such as caspases, cytokines, monocytes, and oxygen-free radicals. These substances poison the chemical environment of surrounding cells, initiating a cascade of degeneration and programmed cell death, called apoptosis. NINDS researchers are studying the mechanisms underlying this secondary insult, which consists mainly of inflammation, toxicity, and a breakdown of the blood vessels that provide blood to the brain. Researchers are also looking for ways to prevent secondary injury to the brain by providing different types of neuroprotection for salvagable cells that prevent inflammation and block some of the toxic chemicals created by dying brain cells. From this research, scientists hope to develop neuroprotective agents to prevent secondary damage.

Basic research has also focused on the genetics of stroke and stroke risk factors. One area of research involving genetics is gene therapy. Gene therapy involves putting a gene for a desired protein in certain cells of the body. The inserted gene will then "program" the cell to produce the desired protein. If enough cells in the right areas produce enough protein, then the protein could be therapeutic. Scientists must find ways to deliver the therapeutic DNA to the appropriate cells and must learn how to deliver enough DNA to enough cells so that the tissues produce a therapeutic amount of protein. Gene therapy is in the very early stages of development and there are many problems to overcome, including learning how to penetrate the highly impermeable blood-brain barrier and how to halt the host's immune reaction to the virus that carries the gene to the cells. Some of the proteins used for stroke therapy could include neuroprotective proteins, anti-inflammatory proteins, and DNA/cellular repair proteins, among others.

The NINDS supports and conducts a wide variety of studies in animals, from genetics research on zebrafish to rehabilitation research on primates. Much of the Institute's animal research involves rodents, specifically mice and rats. For example, one study of hypertension and stroke uses rats that have been bred to be hypertensive and therefore stroke-prone. By studying stroke in rats, scientists hope to get a better picture of what might be happening in human stroke patients. Scientists can also use animal models to test promising therapeutic interventions for stroke. If a therapy proves to be beneficial to animals, then scientists can consider testing the therapy in human subjects.

One promising area of stroke animal research involves hibernation. The dramatic decrease of blood flow to the brain in hibernating animals is extensive - extensive enough that it would kill a non-hibernating animal. During hibernation, an animal's metabolism slows down, body temperature drops, and energy and oxygen requirements of brain cells decrease. If scientists can discover how animals hibernate without experiencing brain damage, then maybe they can discover ways to stop the brain damage associated with decreased blood flow in stroke patients. Other studies are looking at the role of hypothermia, or decreased body temperature, on metabolism and neuroprotection.

Both hibernation and hypothermia have a relationship to hypoxia and edema. Hypoxia, or anoxia, occurs when there is not enough oxygen available for brain cells to function properly. Since brain cells require large amounts of oxygen for energy requirements, they are especially vulnerable to hypoxia. Edema occurs when the chemical balance of brain tissue is disturbed and water or fluids flow into the brain cells, making them swell and burst, releasing their toxic contents into the surrounding tissues. Edema is one cause of general brain tissue swelling and contributes to the secondary injury associated with stroke.

The basic and animal studies discussed above do not involve people and fall under the category of preclinical research; clinical research involves people. One area of investigation that has made the transition from animal models to clinical research is the study of the mechanisms underlying brain plasticity and the neuronal rewiring that occurs after a stroke.

New advances in imaging and rehabilitation have shown that the brain can compensate for function lost as a result of stroke. When cells in an area of the brain responsible for a particular function die after a stroke, the patient becomes unable to perform that function. For example, a stroke patient with an infarct in the area of the brain responsible for facial recognition becomes unable to recognize faces, a syndrome called facial agnosia. But, in time, the person may come to recognize faces again, even though the area of the brain originally programmed to perform that function remains dead. The plasticity of the brain and the rewiring of the neural connections make it possible for one part of the brain to change functions and take up the more important functions of a disabled part. This rewiring of the brain and restoration of function, which the brain tries to do automatically, can be helped with therapy. Scientists are working to develop new and better ways to help the brain repair itself to restore important functions to the stroke patient.

One example of a therapy resulting from this research is the use of transcranial magnetic stimulation (TMS) in stroke rehabilitation. Some evidence suggests that TMS, in which a small magnetic current is delivered to an area of the brain, may possibly increase brain plasticity and speed up recovery of function after a stroke. The TMS device is a small coil which is held outside of the head, over the part of the brain needing stimulation. Currently, several studies at the NINDS are testing whether TMS has any value in increasing motor function and improving functional recovery.

Clinical Trials

Clinical research is usually conducted in a series of trials that become progressively larger. A phase I clinical trial is directly built upon the lessons learned from basic and animal research and is used to test the safety of therapy for a particular disease and to estimate possible efficacy in a few human subjects. A phase II clinical trial usually involves many subjects at several different centers and is used to test safety and possible efficacy on a broader scale, to test different dosing for medications or to perfect techniques for surgery, and to determine the best methodology and outcome measures for the bigger phase III clinical trial to come.

A phase III clinical trial is the largest endeavor in clinical research. This type of trial often involves many centers and many subjects. The trial usually has two patient groups who receive different treatments, but all other standard care is the same and represents the best care available. The trial may compare two treatments, or, if there is only one treatment to test, patients who do not receive the test therapy receive instead a placebo. The patients are told that the additional treatment they are receiving may be either the active treatment or a placebo. Many phase III trials are called double-blind, randomized clinical trials. Double-blind means that neither the subjects nor the doctors and nurses who are treating the subjects and determining the response to the therapy know which treatment a subject receives. Randomization refers to the placing of subjects into one of the treatment groups in a way that can't be predicted by the patients or investigators. These clinical trials usually involve many investigators and take many years to complete. The hypothesis and methods of the trial are very precise and well thought out. Clinical trial designs, as well as the concepts of blinding and randomization, have developed over years of experimentation, trial, and error. At the present time, researchers are developing new designs to maximize the opportunity for all subjects to receive therapy.

Most treatments for general use come out of phase III clinical trials. After one or more phase III trials are finished, and if the results are positive for the treatment, the investigators can petition the FDA for government approval to use the drug or procedure to treat patients. Once the treatment is approved by the FDA, it can be used by qualified doctors throughout the country. The back packet of this brochure contains cards with information on some of the many stroke clinical trials the NINDS supports or has completed.

NINDS-Sponsored Stroke Clinical Trials

Clinical trials give researchers a way to test new treatments in human subjects. Clinical trials test surgical devices and procedures, medications, rehabilitation therapies, and lifestyle and psychosocial interventions to determine how safe and effective they are and to establish the proper amount or level of treatment. Because of their scope and the need for careful analysis of data and outcomes, clinical trials are usually conducted in three phases and can take several years or more to complete.

Phase I clinical trials are small (involving fewer than 100 people) and are designed to define side effects and tolerance of the medication or therapy.

Phase II trials are conducted with a larger group of subjects and seek to measure the effects of a therapy and establish its proper dosage or level of treatment.

Phase III trials often involve hundreds (sometimes thousands) of volunteer patients who are assigned to treatment and non-treatment groups to test how well the treatment works and how safe it is at the recommended dosage or level of therapy. Many of these trials use a controlled, randomized, double-blind study design. This means that patients are randomly assigned to groups and neither the subject nor the study staff knows to which group a patient belongs. Phase III randomized clinical trials are often called the gold standard of clinical trials.

NINDS conducts clinical trials at the NIH Clinical Center and also provides funding for clinical trials at hospitals and universities across the United States and Canada. Below are findings from some of the largest and most significant recent clinical trials, as well as summaries of some of the most promising clinical trials in progress.

Findings From Recently Completed Clinical Trials

Warfarin vs. Aspirin Recurrent Stroke Study (WARSS)

WARSS was a 7-year double-blind randomized clinical trial that enrolled more than 200 patients at 48 participating centers. It was the largest clinical trial ever to compare the benefits of aspirin to warfarin for the prevention of recurrent stroke. Findings from the study were published in the The New England Journal of Medicine (November 15, 2001), which showed that aspirin works as well as warfarin in helping to prevent recurrent strokes in most patients. Whether warfarin was superior to aspirin for stroke prevention was unclear prior to WARSS. Most clinicians believed that warfarin was a better blood thinner than aspirin, although it had three drawbacks: it was more expensive, it required monthly blood tests for proper monitoring, and it had a greater risk for side effects. The WARSS trial demonstrated that aspirin was not only cheaper and safer than warfarin for preventing stroke, it was just as effective – without the additional costs of monthly monitoring.

African-American Antiplatelet Stroke Prevention Study (AAASPS)

The AAASPS study was a randomized double-blind trial that enrolled 1,800 African-American stroke patients at more than 60 sites to compare the benefits of ticlopidine to aspirin in preventing recurrent stroke. A previous clinical trial of ticlopidine had indicated that the antiplatelet drug might be particularly effective for stroke reduction among non-whites, primarily African-Americans. The trial ended early when data analysis suggested that there was less than a 1 percent chance that ticlopidine would be shown to be superior to aspirin if the study were carried to completion. Results showed that 650 mg of aspirin per day is just as effective as ticlopidine in preventing recurrent stroke and has the added benefit of easy availability, lower cost, and less risk for side effects. The findings were published in the Journal of the American Medical Association (June 11, 2003).

Women’s Estrogen for Stroke Trial (WEST)

WEST was the first clinical trial to test the benefits of estrogen therapy for prevention of recurrent cerebrovascular disease in women. The randomized double-blind placebo-controlled trial recruited 664 postmenopausal women from 21 hospitals across the United States. Findings from the study, published in The New England Journal of Medicine (October 2001), demonstrated that hormone replacement therapy with estrogen did not reduce the risk of stroke or death in postmenopausal women who had already had one stroke or transient ischemic attack (TIA, also called mini-stroke). The data also suggested that women who received estrogen were more likely to have a fatal stroke during the first 6 months of treatment, and that their non-fatal strokes were more severe. Based on these findings, the WEST investigators recommended against prescribing estrogen therapy for the purpose of preventing future recurrent stroke in postmenopausal women.

Ongoing Clinical Trials

The Family Intervention in Recovery from Stroke Trial (FIRST)

This study is testing whether or not the daily involvement and support of family, friends, and neighbors can improve the functional abilities of elderly stroke patients. An intervention has been designed to mobilize the social networks of stroke patients to provide effective emotional and practical support. Close to 300 patients from two large city hospitals have been randomly assigned to two groups: one that receives the intervention, and one that receives the usual care. At 3 months and 6 months, members of each group are being assessed for functional ability based both on how well they think they are doing as well as their performance on tests that measure functional abilities. A number of previous studies have indicated that psychosocial interventions can improve emotional adjustment in stroke patients and promote longer survival rates in patients with chronic illnesses. This is the first study to focus specifically on the impact of such psychosocial interventions on physical function in stroke survivors.

The Carotid Revascularization Endarterectomy vs. Stenting Trial (CREST)

The use of dilation and stenting techniques similar to those used to unclog and open heart arteries has been proposed as a less invasive alternative to carotid endarterectomy (a surgical procedure that opens and widens blocked carotid arteries on either side of the neck). This trial is comparing the two techniques for safety and effectiveness. The standard carotid endarterectomy surgical procedure is being used on one set of patients. A procedure that inserts an expanding metal scaffold (stent) into the neck artery after widening it with balloon dilation is being tested on another group. If stenting is shown to be safe, effective, and durable, this less invasive procedure is likely to have a wider application in medical practice. A small add-on study to CREST is using genetic sampling and screening techniques to identify specific genes that could increase the risk for stroke.

Carotid Occlusion Surgery Study (COSS)

The goal of this multicenter randomized clinical trial is to determine if extracranial bypass surgery can reduce the risk of subsequent stroke for a subgroup of people who have a blocked carotid artery and an increased oxygen extraction fraction (OEF, which indicates how hard the brain has to work to pull oxygen out of the blood supply). An increased OEF has been shown to be a powerful and independent risk factor for subsequent stroke – increasing the odds by 25 to 50 percent. Participants have been randomly assigned to medical care with antiplatelet therapy, or antiplatelet therapy in combination with extracranial bypass surgery, which increases blood flow to the brain by using a healthy blood vessel to bypass the blocked artery. The participants are being followed for an average of 2 years to monitor incidence of stroke.

Warfarin vs. Aspirin for Intracranial Arterial Stenosis (WASID)

The goal of this trial is to compare the effectiveness of warfarin to aspirin in preventing subsequent strokes or other vascular-related events, such as heart attacks, in patients with clogged arteries in the brain (intracranial arterial stenosis). This is a randomized multicenter trial that is following two groups of patients who have had a transient ischemic attack (TIA, commonly called a mini-stroke), or a minor stroke caused by blocked or narrowed arteries in the brain. One group is receiving warfarin; the other is taking aspirin. Patients are being followed for 4 years to compare the rates of death due to stroke and vascular-related diseases. This study hopes to show which treatment is better for patients with intracranial arterial stenosis.

Intraoperative Hypothermia for Aneurysm Surgery Trial (IHAST)

Aneurysmal subarachnoid hemorrhage (SAH), in which a bulging artery ruptures and bleeds into the area between the skull and the brain, accounts for only 5 percent of all strokes but has a high rate of mortality and high levels of disability in those who survive. The usual course of treatment is to clip and seal the area around the ruptured artery to end the bleeding and establish normal circulation. The trial investigators believe that this surgical procedure often causes additional neurological damage that can lead to death or substantial disability after surgery. IHAST is a randomized clinical trial designed to evaluate the safety and effectiveness of hypothermia (lowering body temperature to 33 degrees centigrade) to prevent neurological damage during surgery. Patients are being tested 3 months following surgery to establish whether or not there is an improvement in neurological outcome if hypothermia is used during surgery

Extremity Constraint-Induced Therapy Evaluation (EXCITE)

Impaired movement in the arms and legs is a major consequence of stroke. Therapeutic interventions to improve motor function and promote independent use of arms and hands are limited. One technique that has been shown to be successful in basic research studies with animal and human subjects is constraint-induced (CI) movement therapy (also called forced use). The CI technique involves restriction of the less affected arm, while the more affected arm is forced to perform repetitive motions. This trial has randomized stroke patients with at least minimal ability in their arms to two groups – one that receives customary care and one that receives CI therapy. A year after the trial begins, the customary care group will cross over to also receive CI therapy, in order to test whether or not delayed therapy can be effective. Changes in both groups in terms of increased motor function and psychosocial function will be measured.

Warfarin vs. Aspirin in Reduced Cardiac Ejection Fraction (WARCEF)

The purpose of this study is to determine which of two treatments – warfarin or aspirin – is better for preventing death from stroke in patients with low ejection fraction (EF) and heart failure. EF is a measurement that indicates the amount of blood pumped (ejected) from the heart with each beat. Low EF is a known risk factor for stroke in people with heart failure, because the lower the EF, the less blood is being pumped out of the heart. This multicenter (70 sites) study has enrolled thousands of patients with low EF and randomly assigned them to be treated with warfarin or aspirin. Telephone reports and physical exams every 4 months over the course of 3 years have been recording their health status and the occurrence of stroke or other cardiovascular events. Data is also being analyzed for differences in therapy response among men and women, and African-Americans and other racial groups. The study will define the optimal stroke prevention therapy for patients with cardiac failure and
low EF.

Secondary Prevention of Small Subcortical Strokes (SPS3)

This trial is testing the benefits of combined antiplatelet therapy (aspirin and clopidogrel) compared to intensive blood pressure control to prevent recurring stroke in people who have small subcortical strokes (S3). S3, in which the thread-like arteries within cerebral tissue become blocked and halt blood flow to the brain, is the most frequent type of stroke in Hispanic Americans. For those who survive S3, there is a high risk for additional strokes, vascular dementia, and cognitive decline. The trial is enrolling 2,500 patients (20 percent of whom will be Hispanic Americans) who will then be assigned to two interventions: treatment with aspirin and clopidogrel, or intensive blood pressure control. Patients are being followed every 3 months for 3 years. There have been no previous clinical trials focused on the use of combined antiplatelet therapy after S3, on optimal target levels of blood pressure control after stroke, or on prevention of stroke and dementia in Hispanic Americans. The results of this trial will help establish optimal stroke prevention treatment levels for those with S3 and determine if those levels are different for Hispanic Americans.

Field Administration of Stroke Therapy Magnesium Trial (FAST-MAG)

This is a three-phase trial to develop and test methods that can quickly deliver neuroprotective therapies to prevent further damage to brain tissue after stroke. While a number of neuroprotective drugs have been shown to reduce stroke damage to brain tissue in animals, there have been no Phase III clinical trials in humans, mostly because of difficulties in administering the drugs quickly enough. In the first phase of this project, paramedics will immediately administer a neuroprotective agent (magnesium sulfate) to patients with symptoms of acute stroke and the outcomes will be evaluated for safety, practicality, and timesaving over hospital treatment. The second phase is a standard, Phase III clinical trial that randomizes patients to receive either treatment with magnesium sulfate or placebo. The last phase will test differences in outcomes between early treatment before patients reach the hospital versus later treatment in the hospital. If early treatment is shown to be practical as well as more beneficial, a larger multicenter trial can be launched to demonstrate the advantages of administering therapy before patients arrive at the hospital. The results from such a trial could potentially set a new standard of care.

"Stroke: Hope Through Research," NINDS.
Publication date July 2004.

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