ICH Removal: Minimally Invasive Surgery + rt-PA

Purpose
The purpose of this study is to evaluate the use of rt-PA (a clot-busting drug) after a surgical procedure to remove a blood clot from the brain after an intracerebral hemorrhage (ICH). Doctors will compare the new treatment versus standard medical care for ICH.

Introduction
Strokes may be caused by spontaneous (without warning) bleeding into the brain and the formation of a blood clot called an Intracerebral Hemorrhage (ICH). Spontaneous bleeding into the brain can occur in patients with high blood pressure or in the elderly due to fragile blood vessels. If patients are able to survive initially after an ICH; they may suffer with lasting disabilities. These large blood clots take longer to dissolve and may lead to more lasting and severe disabilities. Removing the blood clot in the operating room has been shown to sometimes cause more damage to the brain.

The standard treatment for bleeding into the brain includes giving medications in an effort to control blood pressure and hopefully help to reduce brain tissue swelling caused by the blood in the brain. Standard treatment does not remove the blood clot that has formed in the brain.

Dr. Zuccarello is working with other physicians at Johns Hopkins Medical Center and the National Institutes of Health to conduct research to find out more about the use of rt-PA after a surgical procedure to remove the blood clot from the brain after an ICH. During this procedure, a small tube is placed in the brain where the blood clot is found. A medicine, called rt-PA is given through this tube to break up the blood clot after an ICH.

Why have you been asked to take part in this study?
You are being asked to take part in this research study because you have suffered a stroke caused by bleeding in your brain that has formed a blood clot called an Intracerebral hemorrhage (ICH). You require urgent or immediate medical care for the bleeding in your brain.

Who should not be in the research study?
Potential patients eligible for the study will be identified in the emergency room. You will not be eligible for the study if any of the following are noted during your evaluation:

• Your age is less than 18 years or greater than 75 years.
• You present to the hospital and are diagnosed with an ICH 24 hours after the bleeding event.
• A MRI of your brain shows you have a vascular malformation causing the bleeding in your brain.
• You cannot complete the required 6 month follow-up study visit.
• Your blood pressure cannot be stabilized.
• CT scan of your brain shows an ICH less than 25 millimeters or about 2 and ½ teaspoons (the ICH is too small to treat with this method).
• If the ICH was caused by the blood being too thin such as by use of blood thinning medications.
• If during a six hour stabilization period, your blood pressure cannot be controlled or the bleeding in your brain enlarges.
• If there is a significant rupture of blood into the space in the brain that contains cerebral spinal fluid or this space would get abnormally larger.

Both males and females will be evaluated for this study. Females must be of non-childbearing potential or have a negative pregnancy test confirmed, which will be obtained as the standard of care during the initial evaluation in the emergency room.

All patients must read and sign the informed consent form after the study has been fully explained to be enrolled into the study.

How long will you be in the research study?
Your total duration of participation in the study will be until 6 months after your bleeding event. You will not be required to participate at any other time.

Why is this research being done?
The objective of this study is to evaluate the safety and effectiveness of the drug, rt-PA to break up and remove the blood clot after an ICH.

Who is conducting the research study?
This study is sponsored by the National Institutes of Health. The study is directed by Mario Zuccarello, MD, the researcher at the University of Cincinnati Medical Center.

How many people will take part in the research study?
A total of 80 patients will be treated at 6 medical centers in the United States . Approximately 13-15 patients will take part in this study at the University of Cincinnati Medical Center.

What is involved in this research study?
You will be evaluated to ensure you meet all of the criteria for this study. The evaluation can be completed with the routine care you will receive because you have suffered an ICH to include a:

• complete medical history
• physical examination including neurological examination and vital signs
• CT scan (special x-ray) of your brain
• blood draw to test for blood counts, for pregnancy for all female patients, for kidney function, and minerals and sugar levels in your blood (approximately 3 teaspoon of blood)
• urine test (approximately 2 tablespoons)

Once your physician determines you are a candidate to receive the study drug, you will then be placed by a computer into one of two groups. This process is called randomization. Like the flip of a coin, you will have a 50% chance of being assigned to one of the two groups.

In the medical group you will receive the standard medical care for an ICH which includes medications to control blood pressure and help prevent brain swelling. It is unknown whether the experimental removal of the ICH will lead to a better outcome than the standard medical care.

In the surgical group, your doctor will first give you a medication to numb your scalp. Your doctor will then make a small cut about ¼ inch in the skin on your head and place a hole in your skull over the site of the blood clot to pass a small metal tube, called a drain, into the blood clot. A CT scan will be taken to check for correct placement of the tube in the blood clot. When the tube is in the right place, suction will be applied to the drain to remove as much of the blood clot as possible. Another CT scan will then be performed to see how much of the blood clot remains. If the blood clot is still large, then a soft rubber tube will replace the metal tube in the clot. Your skin will be closed around the rubber tube.

You will be monitored closely and treated by the doctors and nurses in the intensive care unit (ICU). While in the ICU you will be given rt-PA (a drug that breaks up blood clots) through the rubber tube every 8 hours for 72 hours (3 days) or for a maximum of 10 doses, whichever comes first. In between drug doses, the rubber tube will be attached to a drainage system to allow the clot to drain out on its own. After every injection of drug, suction will again be applied to the rubber tube to maximize clot removal.

A CT scan will be done once a day for 3 days to monitor the size of the blood clot. Blood samples (approximately 1 teaspoon) will be drawn for 6 days to monitor for natural chemical levels in the blood related to the bleeding in your brain.

If you are randomized to the medical treatment group, you will receive the standard of care for your ICH to include:

• daily monitoring of your vital signs and neurological condition
• blood drawn (approximately 1 teaspoon) for 6 days to monitor natural chemical levels in the blood related to the bleeding in
  the brain
• A CT scan will be performed daily for 3 days

The rubber tube will remain in place for as long as your doctor feels it is medically necessary, although no further rt-PA will be given after the 72 hours.

Once your doctor determines you are medically stable, you will be discharged from the hospital. Prior to your discharge 2 follow-up out patient appointments will be scheduled for you at 1 month and 6 months after your bleeding event. Each follow-up visit should take approximately 20-30minutes to complete and will be scheduled at the same time you are to see your doctor if possible. Also, at 3 months after the bleed in your brain, you will be called at home and asked questions about your general health and your recovery after the event. The telephone call will take approximately 15 minutes to complete.

What are the risks and discomforts of the research study?
The risks of this study include the chance for a second bleeding event into the brain when:

• the tube is inserted into the blood clot
• when the medicine is given
• when blood is suctioned from the tube
• or when the tube is taken out

Even without any treatment, 35% of patients who suffer an ICH will have a second bleeding event. The risks of a second bleeding event from this procedure are much lower than the natural rate of a second bleeding event.

Other risks of this study involve:

• infection
• worsening neurological condition such as confusion, arm or leg weakness/paralysis, difficulties with speech and/or swallowing,
  and coma
• death

Unlike the standard medical therapy, surgery may injure the brain during the placement of the drain and the suctioning of the clot. Every effort will be made by your doctor to place the drain to prevent damage to the brain.

Infection can occur due to the placement of the drain and leaving it in place for 3 days or for as long as your doctor feels it is medically necessary. All procedures will be performed under the utmost sterile conditions to minimize this risk.

The radiation exposure from the CT scans you will receive by participating in this study is equivalent to an exposure of 1.08 rems to your whole body. For comparison, naturally occurring radiation from the environment exposes people to about 0.3 rems per year and people exposed to radiation in their occupations are permitted to receive whole body exposures of 5 rems per year (50 days in the sun). All precautions will be taken to minimize unnecessary exposure to this radiation, e.g. genital shields if indicated.

Collecting blood samples from your arm may cause pain, bruising, lightheadedness, and, on rare occasions, infection.

There also may be risks and discomforts which are currently unknown or unforeseeable.

Are there any reproductive risks?
Because the risks of this procedure and drug to a fetus are unknown, pregnant women or breastfeeding mothers will not be included in this study. A pregnancy test will be performed for all women of childbearing potential to minimize this risk.

Are there benefits to taking part in the research study?
There is no guarantee that you will receive any benefits from being in this study. The investigators hope to show that rt-PA when given into the blood clot will decrease the size of the blood clot in your head allowing you to recover faster and with less disability. If you are randomized to the medical-treatment group, you may not have this benefit.

The results of this study could be of benefit to many more patients in the future who have bleeding into the brain by providing information on the best way to treat blood clots in the brain.

What other choices for care are there?
Participation in this research is entirely voluntary. You may refuse to participate or withdraw at any time without jeopardizing the medical care you will receive at this institution.

If you decide not to enter this study, currently the only alternative to this treatment is standard medical management without removal of the blood clot. You may receive the standard of care for the bleed in your brain without entering this clinical study.

How will information about you be kept private and confidential?
Every effort will be made to maintain the confidentiality of your study records. Agents of the United States Food and Drug Administration (FDA) and the Department of Health and Human Services (DHHS), the University of Cincinnati IRB and its research study staff, the study sponsor, the National Institutes of Health (NIH), the study investigators of the data coordinating center at Johns Hopkins Medical Center, and governmental agencies in other countries where the study drug may be considered for approval, will be allowed to inspect sections of your medical and research records related to this study. The data from the study may be published or presented in meetings; however, you will not be identified by name. Your identity will remain confidential unless disclosure is required by law. The investigators continue to have ethical and legal obligations to report abuse or neglect and to prevent you from carrying out any threats to do serious harm to yourself or others. If keeping information private would immediately put you or someone else in danger, the investigators would release information to protect you or another person.

What are your costs to be in this study?
The study drug will be provided by the study sponsor. You or your insurance company will be billed for the surgical procedure of placing the catheter into your brain. The hospital fees and doctor’s fee including any other procedures, medications, and testing for your diagnosis will be billed to you and your insurance company as well.

Will you be paid to participate in this research study?
No compensation will be paid to you for participation in this trial.

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.  The University of Cincinnati will decide on a case by case basis whether to reimburse you for your out of pocket health care expenses.  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 benefits to you. You have been told that your doctor has the right to withdraw you from the research at any time without regard to your consent if he or she feels that it is in your best interest or you are not following the study procedures. The study sponsor also has the right to terminate the study at any time.

If during the course of the trial, significant new information becomes available that may be of interest to you or may influence your decision to continue participation in the trial you will be made aware by your doctor. 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 do you call if you have 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 513-475-8624.

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-Cliver, RN (Study coordinator)

University of Cincinnati Medical Center
222 Piedmont Avenue, #3100
Cincinnati , OH 45219
Telephone: 513-558-5398
Fax: 513-558-7702
Email: suzanne.kempisty-cliver@uc.edu

More information
More info is available for this study.
Understanding clinical trials

Study design:
Start date: 6/2004
Close date: upon enrollment of 60-65 patients.
Sponsor: National Institute of Health (NIH)
Study ID number: UC IRB Study 02-09-17-05