Prevention of Vasospasm after Aneurysm Rupture
Overview
The purpose of this study is to measure how effective three different doses of the drug clazosentan are in preventing vasospasm (narrowing of arteries) after an aneurysm rupture.
Introduction
An aneurysm is a balloon-like bulge or weakening of an arterial wall. As the bulge grows it becomes thinner and weaker. It can become so thin that it bursts or leaks. The rupturing of an aneurysm releases blood into the spaces around the brain causing a subarachnoid hemorrhage (SAH), a type of stroke and a life-threatening situation. As soon as a doctor confirms that a blood vessel in the brain has burst it may be necessary to operate on it to stop the bleeding.
A common complication of SAH is vasospasm, which is a narrowing (spasm) of an artery that may occur 4-14 days after the initial bleed and can starve the brain of oxygen, and damage the brain in a similar way to that seen in patients who have had a stroke. Clazosentan (the study drug) may have a specific effect on blood vessels of the brain, causing them to dilate, and so preventing the brain damage that can occur due to narrowed blood vessels. It has been given to healthy people as well as patients with subarachnoid hemorrhage. Although the patient study was only in 34 patients, the results showed that clazosentan could prevent the vasospasm and improve the blood supply to the brain. Clazosentan is not approved by the Food and Drug Administration for the treatment of vasospasm after a brain hemorrhage.
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 brain hemorrhage and are at least 18 years of age and no greater than 70 years.
How long will you be in the research study?
You will be in the research study for approximately 12 weeks.
Who is conducting the research study?
This study is sponsored by Actelion Pharmaceuticals Ltd. The study is directed by Mario Zuccarello, MD, the researcher at Mayfield Clinic and The University Hospital.
How many people will take part in the research study?
About 30 people will take part in this study at The University Hospital. A total of 400 patients will take part in approximately 70 hospitals in 13 countries. Men and women will be included in this study.
What is involved in the research study?
Most of the study procedures conducted in this trial are part of the routine care that you would receive while you are in the hospital, whether or not you participate in this research study. You will be asked to come back after 6 weeks, 10 weeks, and 12 weeks to see how you are doing. Arrangements will be made by your study doctor.
If you agree to be in this study by signing this consent form, the following will occur.
Information will be collected from you at screening. As part of the screening process, you will have a pre-study evaluation to include the following:
- a full medical history
- a full medical examination
- an electrocardiogram (EKG- a tracing of the electrical current in the heart muscle)
- a blood sample will be taken (approximately 5 tablespoons) for routine blood tests and a pregnancy test for all women able to become pregnant
- a CT scan (special x-ray) of your brain to confirm the subarachnoid hemorrhage.
- an angiogram (an x-ray done with dye injected into the bloodstream to see the blood vessels in the brain)
Once it is determined by the study doctor you are eligible for this study drug, you will be "randomized" into one of the study groups described below. Randomization means that you are put into a group completely by chance. It is like flipping a coin. There are four different treatment groups to which you can be placed:
- Group 1- will receive 1mg/hr of study drug, clazosentan
- Group 2- will receive 5mg/hr of study drug, clazosentan
- Group 3- will receive 15mg/hr of study drug, clazosentan
- Group 4- will receive a placebo (an inactive substance)
You will have a 3 in 4 chance of receiving the study drug.
The study drug or placebo will be administered as a solution that is given into a vein, usually in an arm. The treatment will be given all day and all night for a maximum of 14 days. Neither you nor your doctor will know to which treatment group you are assigned to receive. However, if necessary, you doctor will be able to find out which you are receiving.
Depending on what your doctor thinks is best for you, the study drug or placebo could be started either before or after any treatment you need to repair the blood vessel that burst.
While you are receiving the study drug or placebo, your pulse, blood pressure, and temperature will be measured frequently and recorded at least every 6 hours as part of the study procedures. Routine blood tests will be performed daily while you are in the intensive care unit and every other day while you are on a general hospital floor. The amount of blood taken from you for the purposes of the study will not exceed 5 teaspoonfuls per day.
Another CT scan of your head will be performed at 24 to 48 hours to make sure that there are no complications. Approximately 9 days after the original bleeding occurred in your brain, a second angiogram will be performed to see if there is any vasospasm. If symptoms of vasospasm occur before 9 days, an angiogram will be performed then instead and the angiogram at day 9 will no longer be required. An additional angiogram will be performed after 9 days, if your doctor suspects by examining you that you may have developed vasospasm.
If vasospasm has been confirmed, the study treatment may be discontinued if you receive some additional medications or procedures which have not been tested in concurrent use with the study drug.
On the 14th day after the original bleeding occurred in your brain, the study drug will be stopped and the following tests will be performed:
- a physical and neurological examination to include a check of the strength in your arms and legs, your memory and your ability to answer questions appropriately,
- an electrocardiogram (EKG),
- blood pressure, heart rate, and body temperature will be recorded,
- a blood sample (approximately 5 teaspoons) will be taken for routine testing.
- a pregnancy test will be performed in all women able to become pregnant.
6 weeks after your hemorrhage, you will undergo one more CT scan of your head to check for signs of stroke. During this out-patient visit, your doctor also will perform a neurological examination.
10 weeks after your hemorrhage, all male patients that qualify will come back for a semen analysis. The study doctor will discuss the details of this procedure with you. At the same visit, a blood sample, (approximately 5 teaspoons) will be taken to check levels of reproductive hormones.
12 weeks (3 months) after your hemorrhage, you will be scheduled for your last study visit. During this visit, your doctor or the nurse will examine you to check how well you are doing and you will be asked to complete a short questionnaire about your quality of life. During this visit, you also may be interviewed to evaluate how well you have recovered. Male patients who qualify will undergo another semen analysis and also a blood sample (approximately 5 teaspoons) will be taken to check levels of reproductive hormones. At about the same time, your caregiver and/or yourself will receive a phone call during which you or your caregiver will be asked some questions about your wellbeing and how your life has changed, if at all, from the time preceding the bleed in your brain. It is very important for this study to know how you are recovering, so please do your best to be available or have your caregiver available for that call. The interviewer who will call is specifically trained to conduct the follow-up phone interview. Once you are entered into the study, the study nurse will release your contact information to the interviewer, so that you can be contacted.
What are the risks and discomforts of the research study?
The study medication and procedures involve risks and discomfort. As clazosentan is a new treatment, the side effects are as yet unknown. However, you will be informed about any new findings that may affect your willingness to continue receiving the study medication.
In animals, clazosentan produced injury to the heart and arteries supplying the heart and other organs. In general, these findings occurred even at the lowest doses tested. It is not clear if these findings go away after the treatment is stopped. The relevance of these findings to humans is not known; however, it is possible that you may experience similar effects.
A medication called Nimodipine, is given as standard care to treat patients after a SAH. The combination of clazosentan and nimodipine has not been thoroughly tested in animals.
There is a slight risk of pain or bruising when the intravenous (into the vein) lines are in place or when blood is drawn for laboratory tests. There is the risk that you may develop a headache.
The dye that is used to highlight the vessels on x-ray during the angiogram may produce a feeling of warmth or flushing. The most difficult part of the procedure may be lying flat for several hours (up to 2 hours). There is also the risk of an allergic reaction to the dye that you receive during the angiogram. You should inform your doctor if you know of any allergies you may have, especially to iodine, shellfish, or strawberries.
CT scanning causes no pain but does require that you lie still in the machine while the pictures of your brain are being taken. Having an EKG done causes no pain but does require that you lie still while your heart is being assessed.
WHAT ARE THE REPRODUCTION RISKS?
The safety of clazosentan (the study drug) during pregnancy is not known. Research in animals shows that clazosentan can cause abnormalities of the embryo/fetus. Clazosentan has been shown to produce malformations (e.g. cleft palate) in the offspring of rabbits treated during pregnancy. The effect on a human embryo/fetus is not known but may be harmful. You cannot take part in this study if you are pregnant. If you are a woman who is able to have children, you must
use a reliable form of birth control throughout the study and for at least 12 weeks after you stop taking the study medication. Breast-feeding is not recommended during that period.
Therefore, you can only participate if you are postmenopausal (minimum age 50 years old with complete absence of menstruation for at least 2 continuous years), or surgically or naturally sterile or, if you use a reliable method of contraception. Reliable methods of birth control are female/male condoms, diaphragms, and contraceptive sponges only if used in combination with a spermicide or intrauterine devices. Please note that hormone-based contraceptives (regardless of whether they are oral, injectable, or implantable) must be used only in combination with a barrier method (e.g. female/male condoms, diaphragms, and contraceptive sponges). The rhythm method, abstention, or contraception by your partner alone are NOT reliable methods of contraception.
It is recommended that you as a woman should continue to avoid pregnancy for at least three months after stopping the trial medication. If you suspect that you are pregnant, you should inform your doctor immediately.
Compounds of the same class as clazosentan have been linked to the development of testicular injury in animal studies with chronic use. Current data does not allow any conclusion regarding reversibility, but in the cases where it has been examined in animals it has been irreversible.
In animal studies, clazosentan, at doses comparable to the proposed highest maintenance dose in the clinical study, caused mild microscopic (only seen with a microscope) injury to the testes and changes in the sperm. The relevance of these findings to humans is unknown; however, infertility (being sterile) is a possible outcome of this treatment.
Adequate human studies to assess the effects of clazosentan on male fertility (the ability to cause a pregnancy) have not been performed. Therefore, it is possible that sperm may be damaged and the damage may not be reversible once the drug is stopped. To assess the effect on male fertility, men will provide semen samples for sperm analysis and blood samples to check the level of reproductive hormones. These evaluations will take place at 10 and 12 weeks after the bleed. You will be asked to return for scheduled follow-up visits until the results of the semen and blood tests return to normal.
Are there benefits to taking part in the research study?
If you agree to take part in this research study, there may not be a direct medical benefit to you. The investigators hope the information learned from this research study will benefit other patients with subarachnoid hemorrhage in the future.
What other choices for care are there?
All the usual methods for managing vasospasm will be made available to you if you do not wish to participate in this 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, the Mayfield Clinic, Inc, the University of Cincinnati , and the Study Sponsor,Actelion Pharmaceuticals, Ltd, and the Clinical Research Associates will be allowed to inspect 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 your costs to be in this study?
The study drug, the follow-up visits, and all the laboratory testing related specifically to the study will be provided free of charge.
Will you be paid to participate in this research study?
You will not be paid for your participation in the study.
What compensation is available in case of injury?
In the unlikely event that you suffer an injury as a result of your participation in this study, your doctor will provide usual, customary, or in-patient (hospitalized) medical care. If this occurs, you will not be financially responsible for medical expenses for injuries occurring as a result of your participation in this study, beyond those routinely covered by your insurance. In the case of an injury that is a direct result of treatment or study procedure, only your medical expenses will be covered by the Sponsor’s Insurance. No other compensation is offered.
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. 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. M. 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, 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: multi-center, international, double-blind, randomized, placebo-controlled, parallel-group, dose-finding study
Start date: 6/2005
Close date: upon enrollment of 30 patients.
Sponsor: Actelion Pharmaceuticals Ltd.
Study number: UC IRB Study #05-3-3-3, Sponsor Study #AC-054-201 |
