Prevention of Disability after Spinal Cord Injury

Overview
The purpose of this study is to determine the most effective dose of the drug Cethrin® to prevent cell death after a spinal cord injury. The drug is applied to the protective lining of the spinal cord, called the dura mater, during surgery to stabilize the spine.

Introduction
Spinal cord injury occurs in an instant and can transform an individual into a person who must live with a permanent disability, without autonomy, and with severe co-morbidities. Protected by the bony spinal column, the spinal cord is the information super-highway linking the body and the brain. Trauma to the spinal cord affects body areas below the injury level. An injury can be either complete or incomplete, depending on the extent of nerve damage. Standard treatment typically includes surgical stabilization of the injured site and high-dose steroids to prevent spinal cord swelling. There remains a great-unmet need for treatments that reduce the damage and disabilities associated with spinal cord injury.

After injury to the spinal cord, neurons that are damaged do not regenerate their severed axons -- the long fibers of communication between the brain and spinal cord that carry sensation and movement signals. Additionally, there is an abnormal activation of the protein Rho, which causes cell death. In research done on animals, the drug BA-210 (Cethrin®) helped repair the spinal cord after an injury by preventing nerve cell death and stimulating the cells to re-grow their axons. The mechanism of action of Cethrin® is understood to block activation of Rho, a key protein that regulates both regeneration and cell survival. It is hoped that Cethrin® will have the same effect on the spinal cord of humans, but this has not yet been tested until now.

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 are between the age of 18 and 70 and have suffered a severe spinal cord injury to either your upper back called a thoracic injury or your neck area called a cervical injury, that requires spinal surgery within 7 days of your injury.

How long will you be in the research study?
You will be followed for 6 months after your surgery. The study doctor may decide to take you off this research study at any time if he feels it is in your medical best interest. You will only be required to participate after the 6-month period if you have an adverse reaction or complication that occurs during that time. In that case you will then be followed until the event is resolved or stabilized.

Who is this research being done?
The purpose of this trial is to determine the safety of the study medication, Cethrin®, when given at the time of spinal surgery. This research will also evaluate how the study medication works in your body. Cethrin® is an investigational drug not presently approved by The United States Food and Drug Administration.

Who is conducting the research study?
This study is sponsored by, BioAxone Therapeutique, Inc. and is directed by Charles Kuntz, IV, M.D., the researcher at the University of Cincinnati.

How many people will take part in the research study?
Up to 10 different sites in the US and Canada will take part in the study. A total of up to 48 subjects will take part in all. At the University of Cincinnati, up to 6 subjects will be enrolled.

What is involved in the research study?
The study doctor will assess your current symptoms and condition as a result of your spinal cord injury. Your medical history including any medications you are taking will be recorded and a physical examination will be performed. You will have the following procedures done:

• Blood samples will be drawn (approximately 1 tablespoon).
• If you are a female able to have children, you will also have blood drawn for a pregnancy test.
• CT scan (special x-ray) of your head, abdomen and area of your spine where you suffered the spinal cord injury will be taken.
• MRI (image obtained with a special magnet) of your head and the area of your spine where you suffered the injury will be taken. This is standard care for the injury you have suffered.

Once your surgeon has determined you are a candidate to receive this study medication Cethrin® you will be placed into 1 of 4 groups as follows:

• Group 1 will receive Cethrin at a dose of 0.3 mg
• Group 2 will receive Cethrin at a dose of 1 mg
• Group 3 will receive Cethrin at a dose of 3 mg
• Group 4 will receive Cethrin at a dose of 6 mg

The dose you receive will depend on the time you are recruited into the study. First patients will receive the lowest dose of 0.3 mg, and then those enrolled later will receive the next doses. The next dose will not be given until the Safety Monitoring Board reviews the results from the previous groups and determine the dose is safe.

You will then be scheduled for spinal surgery. You will have the same type of surgery whether or not you are part of this research. You will not be required to participate in any extra surgical procedures. At the end of your surgery, the study medication, Cethrin®, will be applied to a thin layer of tissue called the dura matter that covers your spinal cord before the final stitches are made to close your incision. The study medication will be combined with a fibrin sealant to ensure it stays in place. Fibrin sealants are approved, marketed products used for tissue sealing or to stop bleeding. They are commonly used during surgery after spinal cord injury.

After your surgery you will be transferred to the Intensive Care Unit (ICU). While in the ICU you will have a physical examination and blood drawn daily as per the standard of care for patients that have suffered a spinal cord injury. Also, your vital signs will be monitored closely. You will remain in the ICU for at least 3 days or longer until you are medically stable for discharge as decided by your surgeon. You will also have a follow-up MRI scan of your spine to check the surgical site on day 4 (72 to 96 hours) after your surgery. This is standard care for the injury you have suffered. A neurological test will also be done between 24 and 72 hours after the surgery.

After surgery you will also have blood drawn at a half hour after the placement of the study medication, Cethrin®, and then at 1, 2, 6, 24, and 48 hours after the placement of the study medication. At each time approximately 1 teaspoon of blood will be drawn. These blood draws are not standard of care.

At 10 days and 3 weeks after your surgery, your vital signs (body temperature, blood pressure, and pulse rate) will be recorded and a physical examination will be performed. Your doctor will examine your surgical site. In addition, you will have blood samples taken for laboratory tests. The 3-week visit is not considered standard care and is for research purposes only. You will be asked how you are feeling and about any medications you have taken.

At 6 weeks after your surgery, your vital signs will be recorded and a physical examination will be performed. Your doctor will examine your surgical site and perform neurological tests. In addition, you will have blood samples (approximately 2 tablespoons) taken for laboratory tests and an MRI of the head and the injury area. You will be asked how you are feeling and about any medications you have taken. If you withdraw from the study early (early termination), the tests scheduled for 6 weeks after your surgery, should be performed at the time of withdrawal.

At 3 months and 6 months after your surgery, your vital signs will be recorded and a physical examination will be performed. Your doctor will examine your surgical site and perform neurological tests. In addition, you will have blood samples taken (approximately 2 tablespoons) for laboratory tests. You will be asked how you are feeling and about any medications you have taken.

What are the risks and discomforts of the research study?
All spinal cord injury treatments may cause undesirable effects.
The most likely risks associated with this study are expected to be:

Problems related to the fibrin sealant. The most common problem is allergic reactions. Some of the proteins in the fibrin sealant come from beef, and some patients have had allergic reactions (developing a rash or having trouble breathing) to these proteins.

• Problems related to Cethrin® include:
• Results from studies in animals suggest that problems may include renal dysfunction (kidney trouble), severe hypotension (abnormally low blood pressure), inflammation (irritation of tissue), hemorrhage (bleeding), nerve fiber degeneration (a breaking down of the nerve) and liver changes. This will be the first study of Cethrin in humans. With this lack of previous experience, it is possible that unexpected problems may occur.
• Several experiments have been performed in animals including dogs, pigs, rats, and mice using this study drug. Experiments in mice after a spinal cord injury have shown an increased risk of death.

Blood samples will be drawn at all study assessments. Some known risks, although rare, that can be associated with the blood drawing procedure are pain, bleeding, burning, dizziness, fainting, or the development of a bruise or an infection at the site where the needle was placed to draw the blood. The maximum amount of blood that will be drawn on any day of the study is about 15 mL (1 tablespoon). The total amount of blood that will be drawn for the study is about 60 mL (4 tablespoons).

MRIs of your spinal injury area will be performed during the study. An MRI of the head will also be performed. Additional MRIs and CT Scans will be performed if the study doctor feels it is necessary. There are no known risks associated with MRI. Some people find MRIs difficult because of feelings of claustrophobia (fear of being in a small, enclosed space). If you have had such feelings in the past, please discuss this with the study doctor before you undergo the MRI. Sedation can be given to help you undergo MRI more easily.

What are the reproduction risks?
If you are or become pregnant, or if your partner becomes pregnant, there may be unknown risks to the baby. You will be given a pregnancy test before enrollment if you are a woman able to have children, and if the result is positive, you will not be enrolled. If you are at risk of becoming pregnant, you must use a medically accepted form of birth control during the time you are participating in this study. Your doctor will discuss this with you if needed. You must not be nursing an infant during the study. If you are a sexually active male, you must take appropriate actions to avoid pregnancy with any partner.

As with all research studies, the drug treatment and study procedures in this investigation may involve unknown risks. All medications can have both temporary and permanent side effects and can cause unforeseen adverse reactions.

Are there benefits to taking part in the research study?
Cethrin has not been proven to reduce damage to the spinal cord in humans and may not have any benefit for you. If you agree to take part in study there may or may not be direct medical benefit to you. The study drug may improve your spinal cord injury but this is not guaranteed. It is hoped that information learned from this study may help others with spinal cord injuries in the future.

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. There are other methods available to you for treating your spinal cord injury. You may choose to have your planned spinal surgery but not to be in this study; in this case, you will not receive Cethrin.

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 University of Cincinnati, the sponsoring company, BioAxone Therapeutique, Inc., and BioAxone Drug Safety Monitoring Board 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. 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?
You will not be billed for any testing, evaluations, or procedures required by the study that are not part of the standard of care that you would receive related to your injury. You will not be billed for the study drug. The hospital fees and doctor’s fee including any procedures, medications, and testing that are part of the standard of care for your diagnosis will be billed to you and your insurance company.

Will you be paid to participate in this research study?
You will not be paid to participate 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. BioAxone Therapeutique, Inc., 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. 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.

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
Charles Kuntz, IV, MD (principal investigator)
Suzanne Kempisty, RN (study coordinator)

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

More information
More info is available for this study.

Start date: 8/2005

Close date: upon enrollment of 6 patients

Study type: Phase I/IIa Dose-Ranging Study

Sponsor: BioAxone Therapeutique, Inc.

Study ID number: UC IRB Study 05-5-16-2, Sponsor Study BA-210-101

More information: Understanding clinical trials