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. For more
information on excitotoxicity, neuroprotection, and
the ischemic cascade, please refer to the
Appendix.
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: April
2004
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.
Where
can I get more information?
For more information on neurological disorders or research programs
funded by the National Institute of Neurological
Disorders and Stroke, contact the Institute's Brain
Resources and Information Network (BRAIN) at:
BRAIN
P.O. Box 5801
Bethesda, MD 20824
(800) 352-9424
http://www.ninds.nih.gov
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