Carotid Occlusion Surgery Study (COSS)

Overview
The purpose of this study is to determine if a surgical operation called "Extracranial-Intracranial Bypass" can reduce the chance of a subsequent stroke in someone who has complete blockage in one main artery in the neck (the carotid artery) that supplies blood to the brain and has already suffered a small stroke. This surgery involves taking an artery from the scalp outside the skull, making a small hole in the skull and then connecting the scalp artery to a brain artery inside the skull. In this way the blockage of the carotid artery in the neck is bypassed and more blood can flow to the brain.

Why have you been asked to take part in this research study?
You are being asked to take part in this research study because you have been diagnosed with a complete blockage in one of the main arteries in your neck (the carotid artery) that supplies blood to the brain.  You have also been asked because you have suffered a mini stroke (TIA) or a stroke in the same side of the brain as the neck artery blockage within the last 120 days.

Who should NOT be in the research study?
Your surgeon will identify potential patients eligible for the study from those seeking his treatment.

You should not participate in this study if any of the following apply to you:

• You are less than 18, or older than 85 years of age.
• You have a disorder of your blood cells such as sickle cell disease.
• You have a known heart disease (i.e. artificial heart valve, unstable angina).
• You have had a heart attack within the last 6 months.
• You have a serious, advanced, or terminal illness such as cancer.
• You have a neurologic disorder that would make it difficult for the study doctors to evaluate your condition.
• You are pregnant.
• You are currently participating in another experimental treatment study.
• You have participated in an experimental study that included exposure to x-rays within the last 12 months.
• You are allergic to x-ray dye.
• You are allergic to aspirin.
• You have persistently very high or very low blood pressures that cannot be controlled by your doctor.
• You are diabetic and have persistently very high blood sugars that cannot be controlled by your doctor.

How long will I be in the study?
You will be in the research study for at least 2 years and up to six years.  This will include follow-up monthly by telephone and follow-up visits at three-month intervals for the duration of the study.

The researcher may decide to take you off this research study at any time if circumstances arise (i.e., not being able to tolerate a study medication, not following the instructions of the study) which warrant doing so. You will remain under the care of your Primary Care Physician (PCP) through out this study.

Why is this research being done?
The purpose of this research study is to determine if a surgical operation called “Extracranial-Intracranial (EC/IC) Bypass” surgery can reduce the chance of a stroke in someone who has a complete blockage in one of the main blood vessels or arteries in the neck that supplies blood to the brain.  This surgery involves taking an artery from the scalp outside the skull, making a small hole in the skull bone and then connecting the scalp artery to a brain artery inside the skull.  In this operation, the blockage of the artery in the neck is bypassed and more blood can flow to the brain.  In some people natural bypass arteries develop and the brain is getting plenty of blood flow.  These people have a low risk of having a stroke if they take medications.  In other people, no natural bypass arteries develop so less blood flows to their brains.  These people have a 25 to 50% risk of having a stroke while taking medications within the next two years.  It is these people who may benefit from having the EC/IC bypass operation and who may be candidates for this study.  This bypass operation is considered experimental because it is not generally performed for this medical condition and it is unknown if it leads to a decrease, an increase, or no change in the risk of having a stroke. 

Who is conducting this research study?
This research is sponsored by The National Institutes of Health.

How many people will take part in this study?
About 93 people will take part in this study at the University of Cincinnati Medical Center.  A total of 930 people will take part across the country.  This study will be conducted at 20-30 sites.

What is involved in this research study?
In order to determine if you are one of the people who may benefit from the EC/IC bypass surgery, you will need to have two tests.  The first test is called positron emission tomography or PET scan.  This test will be done at the Kettering Medical Center in Kettering, Ohio, which is approximately 45 miles from Cincinnati, Ohio.  The PET scan will measure the amount of blood that is getting to your brain and the amount of oxygen that your brain is using.  The PET scan uses radioactive oxygen and water and is an experimental procedure.  If this PET scan shows that plenty of blood and oxygen are getting to your brain, your participation in the study will be over.  If the PET scan shows that less blood is getting to your brain, you may need the second test, which is called a cerebral arteriogram.  A cerebral arteriogram will provide a map of the arteries of the neck and brain to see if your arteries can be connected.  This test is commonly performed on patients with stroke as standard of care and you may have already had this test.  If you have not had this test or if the arteriogram that you had did not show the arteries well enough, you will need to have an arteriogram for the purpose of this study.  If your arteries cannot be connected, your participation in the study will be over.  If your PET scan shows less blood getting to your brain and your arteriogram shows your arteries can be connected, you will be eligible for the study.

You will be “randomized” into one of the study groups that will be described below.  Randomization means that you are put into a group completely by chance.  In this case, it is like flipping a coin and you will have a 50-50 chance of receiving the bypass surgery or not and then agree to return for follow-up visits one month later and then every three months for at least two and possibly up to six years.

Your participation will involve the following four steps:

Step 1: PET Scan

• Before having the PET scan, you will undergo a medical history and examination, an electrocardiogram (ECG) to get a picture of the electrical action of your heart and have approximately two tablespoons of blood drawn from a vein in your arm for blood tests on your first visit.  Blood drawn for purposes of this study will not be used for genetic research.
• You will be scheduled for a PET scan at Kettering Medical Center in Kettering, Ohio.  The PET scan is for the measurement of blood flow and oxygen use in your brain with a special radiation detection camera called a positron emission tomographic (PET) scanner.  At the time of the PET scan, an intravenous line will be started for drawing approximately four tablespoons of blood for blood tests and for the administration of the radioactive water for the scan.  Your pulse rate, respiratory rate, and blood pressure will be monitored throughout the procedure. You will lie on your back and your head will be positioned inside the scanner.  During each PET study you will breathe once or twice air that contains a small amount of radioactive oxygen and receive once or twice an intravenous injection of radioactive water.
• If your PET scan shows that plenty of blood and oxygen are getting to your brain, your participation in the study will be over and you will not require any further follow-up or treatment as part of the study. 
• If your PET scan shows that less blood is getting to your brain you will go on to Step 2.

Step 2: Arteriogram

• If you have not already had an arteriogram that shows all the important blood vessels in your brain, you will undergo this test.  An arteriogram involves a puncture of an artery in the groin, and uses x-rays to guide a small tube into the arteries through the body leading to the brain.  X-ray dye will be injected through the small tube in to the artery of your brain.  The dye will spread to the arteries in your neck and head and pictures will be taken of this area. The tube will be removed from your groin and pressure will be applied to the puncture site for at least 15 minutes.  You will be carefully watched during and after the procedure for any complications. The surgeon will use these pictures to decide if an artery in your scalp can be safely connected to an artery in your skull.
• If your arteriogram shows that your arteries cannot be connected, your participation in the study will be over.  You will not receive any further follow-up or treatment as part of this study.  You will be referred back to your primary care physician for any further treatment.

Step 3: Assignment and Performance of EC/IC Bypass Surgery

• If your arteriogram shows that your arteries can be connected, you will randomly assigned by chance like the flip of a coin to receive the bypass surgery or not.  You will be one of approximately 400 people across the country who will be randomly assigned to receive the bypass surgery or not as part of this study.
• If you are assigned to the surgery group, the surgeon will decide whether your medicines need to be changed to reduce the risk of bleeding at the time of surgery. If you are taking anticoagulant medications (“blood thinners”) or certain other medicines that keep the blood from clotting, you will need to replace these medicines with aspirin for a period of time before and after the surgery. You will undergo “Extracranial-Intracranial Bypass (EC/IC)” surgery. This surgery involves shaving your head on the side where the artery has been found to be blocked. An incision will be made in the area in front the ear up to the top of the ear. This incision may be rather large. After the incision is made the surgeon will take a blood vessel called an artery from the scalp outside the skull, making a small hole in the skull and then connecting the scalp artery to a brain artery inside the skull.  In this way the blockage of the artery in the neck is bypassed and more blood can flow to the brain. The incision will be closed and bandaged. There may be pain and swelling at the site of the incision and you may not be able to lie on this side of your head for a few days after surgery. This surgery will be done while you are under general anesthesia (asleep) and will require that you stay in the hospital for several days afterward.
• If you are not assigned to surgery, you will remain on the medicines prescribed by your doctor.

Step 4: Follow-Up Clinic Visits

• If you are assigned to the surgery group, you will come back at approximately one month after your surgery for a one-hour clinic visit, then for a one-hour clinic visit two months later and then every three months after that for a minimum of two years and as long as six years.  You will also be scheduled at one month for a repeat PET scan at the Kettering Medical Center in Kettering, Ohio.  At each clinic visit, a medical check-up will be performed and recommendations to your PCP will be made regarding the best medicines for you to take to reduce your risk of having a stroke.  Approximately two tablespoons of blood will be drawn for tests, an electrocardiogram will be done and the bypass surgical site will be checked by placing an ultrasound probe on the skin.
• If you are not assigned to surgery, you will come back one month later for a one-hour clinic visit, then two months later and every three months after that for a minimum of two years and as long as six.  At each clinic visit, a medical check-up will be performed and recommendations to your PCP will be made regarding the best medicines for you to take to reduce your risk of having a stroke.  Two tablespoons of blood will be drawn for tests and an electrocardiogram will be done.  These check-ups and the advice from the doctor about reducing the risks of stroke will be free.
• For the duration of the study, you and/or your next-of-kin will agree to notify the study investigators of any change in your health status and to consent to the release of all your medical records to the study investigators.

Arteriograms are a standard medical test sometimes performed in people with blockage of the main arteries in the neck (carotid arteries) as part of standard medical care to ensure that the blood vessel is completely blocked and cannot be opened up by an operation on the neck.  The PET scan and the EC/IC bypass surgery are experimental procedures.

What are the risks and discomforts of the study?
There are certain risks and discomforts that may be associated with this research.  They include:

Pet Scan:

• Rare: This research involves exposure to radiation from the PET Scans and the arteriogram, if necessary.  The maximum amount of radiation you will receive from the procedures (one arteriogram is approximately 1230 mrems) and possibly two PET scans (approximately 750 mrems each) when averaged over the entire body is approximately 2730 mrems.  This is equivalent to one-half of the allowable yearly dose to radiation workers such as x-ray technicians.  The risk from the radiation exposure in this study is too small to be measured and is small when compared with other everyday risks encountered.

Arteriogram:

• Common: If required, can cause some discomfort and bruising at the groin puncture site. The dye may cause a warm sensation through out your body. An increase in urination to remove the dye from the body. 
• Rare: The major risk of an arteriogram is a stroke.  Some strokes are minor and some can lead to death or permanent loss of the ability to see, speak, or move.  Kidney failure, tear in an artery are also possible with this procedure. Other potential complications include bleeding or infection at the arteriogram puncture site.  Generally, complications like these occur in less than 3% of all patients having an arteriogram.
• Rare: Mild allergic reactions to x-ray contrast material may occur in up to 2 to 4% of patients having an arteriogram.  Severe reactions to x-ray contrast occur in 1 case in 1000.

EC/IC Bypass Surgery:

• Common: Surgery, if required, can cause some discomfort on the side of the head of the surgery.  You will have some swelling of the skin at the site of the surgery.
• Uncommon: There is a risk of both stroke and death from the extracranial-intracranial (EC/IC) bypass surgery.  Some strokes are minor and some can lead to death or permanent loss of the ability to see, speak, or move.  In one large study, the risk of non-fatal stroke was one in thirteen (7.6%) and the risk of death was one in one hundred (1%) during surgery and within the next month.  We anticipate the surgical risks in this study will be the same but may be greater or less.
• Rare: There are many rare complications of the bypass surgery that are usually, but not always, less serious than stroke.  These include bleeding and infection in the scalp and brain.  These complications may require an emergency operation and can lead to damage of the brain or even death.  In addition, some patients may suffer a heart attack or develop pneumonia during or after the surgery.  Both can be fatal.

Venipuncture:

• Common: The risks of common venipuncture includes, discomfort and/or bruising where the needle enters the skin. An intravenous catheter will be placed in the forearm or hand for each PET scan, the arteriogram if required, and the surgery if assigned.  In addition, blood will be collected for tests at each medical check-up. 
• Uncommon: The formation of a small blood clot or swelling of the vein and surrounding tissue, bleeding from the puncture site and nerve injury.

There also may be risks and discomforts, which are not yet known.

Are there any reproductive risks?
If you are a woman able to have children, you should understand that some research medications or procedures can affect an unborn baby.  If you are pregnant, think you are pregnant, or if at any time during your study participation there is a lapse in your birth control procedures, it is important for you to notify the study investigator immediately.  On the day of your scheduled PET scan, arteriogram if required, and surgery if assigned, you must be willing to have a pregnancy test done or at any other time throughout the study at the discretion of the investigator.  

Are there any benefits in taking part in this research study?
If you agree to take part in this research study, there may not be a direct medical benefit to you.  We hope the information learned from this research study will benefit other patients by determining if EC/IC bypass surgery can reduce the risk of stroke in patients with complete blockage in one main artery in the neck (carotid artery occlusion) that have the highest risk of stroke.  It may provide information that can be used to prevent stroke in other patients in the future.

Potential benefits to you may include:
If your PET scan shows that plenty of blood and oxygen is getting to your brain, then you will know that your chance of having a stroke within the next two years while taking medication is low or about one in twenty (5%).  If your PET scan shows that less blood is getting to your brain, you will have a 50-50 chance, like tossing a coin, of receiving the bypass surgery or not.  Even adding in the risk of stroke due to the surgery and arteriogram if necessary, EC/IC bypass surgery has the potential to cut in half your chances of having a stroke during the next two years, from one in three to one in six.  We do not know if this will be the case.  The surgery may have a greater benefit, a lesser benefit, no benefit at all or even increase your chances of having a stroke.  Whether you receive the surgery or not, you will receive recommendations regarding the best medicines for you to take to reduce your risk of having a stroke.

What other choices for care are there?
Instead of being in this research study, you have these options:
Standard medical practice at this time is to treat complete blockage of the carotid artery with medicine that reduces the risk of blood clots causing stroke.  You may choose to continue on medical treatment to prevent stroke as prescribed by your own physician.  PET scan to measure blood flow to the brain is only done as part of research studies, but there are other tests available that measure how well blood gets to the brain.  EC/IC bypass surgery is considered an experimental procedure but is performed by some neurosurgeons. 

How will information about you be kept confidential?
Every effort will be made to maintain the confidentiality of your study records.  Agents of the United States Food and Drug Administration and other National regulatory authorities, the University of Cincinnati, designates of the National Institute of Health, representatives of COSS, and the Greater Cincinnati/Northern Kentucky Stroke Team will be allowed to inspect and copy sections of your medical and research records related to this study.  The data from the study may be published; however, you will not be identified by name.  Your identity will remain confidential unless disclosure is required by law.

What are the costs of being in this study?
Funds are not available to cover the costs of any ongoing medical care and you will remain responsible for the cost of non-research related care.  All the procedures described above (PET scans, an arteriogram, EC/IC bypass surgery, and study follow ups) will be provided at no cost to you.  Other costs incurred solely for purposes of research will not be your financial responsibility.

You will not be paid for participation in this research study.  You will be compensated per follow-up visit for your costs (i.e.: transportation, mileage, parking, for PET scan visit you will also be reimbursed for minimally priced meal for patient and caregiver).

What compensation is available in case of injury?
In the event that you become ill or injured from participating in this research study, emergency medical care will be provided to you.  All charges for non-research related medical care provided to you will be billed to you or your insurance company.  You will remain responsible for any charges not paid by your insurance company for such injury or illness.  No other compensation is available.

What are your rights as a participant?
You may choose either to take part or not to take part in this research study.  If you decide to take part, you may decide to leave the study at any time. Leaving the study will not result in any penalty or loss of benefit to you. The investigators will tell you about new information that may affect your health, welfare, or willingness to stay in this study.

If you have questions about the study, you will have a chance to talk to one of the study staff or your regular doctor.  Do not sign this form unless you have had the chance to ask questions and have received satisfactory answers.

Nothing in this consent form waives any legal rights you may have nor does it release the investigator, the sponsor, the institution, or its agents from liability for negligence.

Who to call if you have any questions or problems?
If you have questions about this research study or to report a research-related injury, you can contact the researcher Dr. Mario Zuccarello at 513-558-3590.

If you have general questions about giving consent or your rights as a research participant in this research study, you can call the University of Cincinnati Medical Institutional Review Board at 513-558-5259.

Location & contact
Mario Zuccarello, MD (Principal Investigator)
Suzanne Kempisty, RN (Study coordinator)

University of Cincinnati & Mayfield Clinic
Telephone: 513-558-3590
Fax: 513-558-7702
Email: suzanne.kempisty@uc.edu 

More information
Understanding clinical trials