DURHAM, N.C. (Ivanhoe Newswire) - It can happen in an instant and change lives forever. Close to two million people are affected by traumatic brain injury every year. Worldwide, it's a major cause of death and disability. Now, researchers are hoping something that our body produces naturally can help bring the first ever TBI treatment to those who need it.
"As I was driving, I blacked out behind the wheel and the car went into the back of a parked 18 wheeler," Lester Talley told Ivanhoe.
Health issues led to Lester Talley's near fatal accident. The husband and father of two suffered a serious traumatic brain injury.
"My brain had started swelling," Lester said.
"There really is no definitive therapy for the treatment of acute brain injury," Daniel Laskowitz, MD, MHS, Professor Medicine (Neurology), Neurobiology, & Anesthesiology, and Director, Neurovascular Laboratories at Duke University Medical Center, told Ivanhoe.
Lester's wife Ashley feared the worst.
"Seemed like my world was coming to an end," Ashley told Ivanhoe.
While in a coma, Lester was enrolled in a phase three trial called SyNAPSe. The study is testing if progesterone could help treat TBI. It's a natural hormone produced in men and women, that's most often associated with pregnancy.
"There is good evidence that it reduces inflammation," Dr. Daniel Laskowitz said.
The hormone has to be given within eight hours of an injury. It's infused into the brain for five days straight.
"Also, their ultimate endpoint is how they are doing at six months," Dr. Daniel Laskowitz explained.
Research shows the drug can rebuild the blood-brain barrier and decrease brain swelling and cell death.
The trial is blinded so Lester doesn't know if he got the drug or a placebo, but in six months he's come a long way. He still has trouble with the left side of body and a few memory issues.
"He remembered the most important thing, that I'm his wife. That's what I wanted him to remember," Ashley said.
More than 150 sites in 21 countries are taking part in the SyNAPSe trial. The goal is to enroll more than 1,100 TBI patients. A 2012 review of the first 200 study participants found there were no safety concerns associated with the treatment.
BACKGROUND: Traumatic brain injury (TBI) occurs when an external mechanical force causes brain dysfunction. It usually results from a violent blow or jolt to the head or body. Mild traumatic brain injury can result in torn tissues, bruising, bleeding, and other physical damage to the brain that can result in long-term complications or death. The degree of damage depends on several factors, including the nature of the event and the force of impact. Injury can include several factors: damage to brain cells may be limited to the area below the point of impact on the skull; a blast can cause widespread damage; a severe rotational jolt can cause the tearing of cellular structures; an object penetrating the skull can cause irreparable damage to brain cells, blood vessels, and protective tissues around the brain; or bleeding in or around the brain, swelling, and blood clots can disrupt the oxygen supply to the brain and cause wider damage. (Source: www.mayoclinic.com)
COMPLICATIONS: Severe injuries can increase the risk of a greater number of complications and more severe complications. Moderate to severe traumatic brain injury can result in prolonged or permanent changes in a person's state of consciousness, responsiveness, or awareness. Some people with TBI will have seizures within the first week. Cerebrospinal fluid may build up in the spaces in the brain of some people who have had TBI's, which causes increased pressure in the brain and swelling. Skull fractures or penetrating wounds can tear the layers of protective tissues that surround the brain. This can enable bacteria to enter the brain and cause infections. An injection of the meninges could spread to the rest of the nervous system if not treated. Also, injuries to the base of the skull can damage nerves that emerge directly from the brain. (Source: www.mayoclinic.com)
NEW TECHNOLOGY: Unfortunately, little can be done to reverse the initial damage caused by a traumatic brain injury. Once it occurs, medical treatment focuses on preventing further injury and promoting rehabilitation. There are currently 13 treatments in clinical development for the potential treatment of TBI. Areas of research include progesterone, stem cells, hypothermia, magnesium sulfate 9, calcium iron influx, and progesterone. SyNAPSe (Study of the Neuroprotective Activity of Progesterone in Severe Traumatic Brian Injuries) is a global, Phase 3, multi-center pivotal trial in severe TBI. The study is evaluating the effectiveness of its proprietary BHR-100 progesterone product as a neuroprotective agent for TBI patients. About 1,200 patients with severe, closed-head TBI enrolled in the study at 150 medical centers, including sites in the United States, Europe, Israel, Asia, and Argentina. The treatment is administered as a five-day continuous intravenous infusion. It also has to be administered within eight hours after the injury. (Source: http://www.synapse-trial.com/about-synapse/) Researchers believe the therapeutic agent will provide significant benefits to patients, including efficacious treatment for TBI patients, decreased mortality form brain injury, reduction of direct and indirect health care costs, and reduction of short-term and long-term disability.
Progesterone, also called P4, is a 21-carbon steroid hormone known for its involvement in the female menstrual cycle, pregnancy, and embryogenesis of humans. Discovery of progesterone's neuroprotective properties began with the observation of a gender difference in response to experimentally induced TBI. Researcher Donald Stein and his colleagues noted that female rats recover better than male rats after TBI, which showed them that the hormone might account for the outcomes. (Source: http://www.synapse-trial.com/why-progesterone/)
Daniel Laskowitz, MD, MHS, Professor Medicine (Neurology), Neurobiology & Anesthesiology and Director of Neurovascular Laboratories at Duke University Medical, discusses a new drug helping people with traumatic brain injuries.
What exactly is this study doing? It could have pretty big ramifications as it may be the first drug to help TBI, correct?
Dr. Laskowitz: Yes. At present, there really is no definitive therapy for the treatment of acute brain injury. A lot of what we do is supportive care and we try to reduce intracranial pressures, which are pressures within the skull as the brain swells in the short-term, but there is really no definitive pharmacologic agent that we can give patients. So, this would really represent the first therapy that has been shown to improve long-term outcomes.
Can you explain how devastating it is when you see these patients come in since you were here in 1995 and what it has been like?
Dr. Laskowitz: I work in the neuro-ICU. A lot of what we see in this area is closed head injuries. We do not see as much penetrating or gunshot, although we do see that occasionally. We see a lot of car accidents where you have an acceleration/deceleration injury where your head will hit the windshield and then rock back and kind of rotate on itself. These patients often come in devastated and they are often young people. Steven Jones is a good example: man in his early 20s who has his whole life in front of him and in a moment his life has changed completely. He came in in a coma. Despite our best efforts, we are not very good at prognosticating how patients do and there is a lot of variability in people's individual genetics in terms of how they do as well. Steven was enrolled in the study and we do not know if he got drug or whether he got placebo, but he did well. He went to rehab within a month, but often these people's lives are changed completely even if they survive the initial injury, and often they do not. When a patient is presented as severe as he did with a very significant brain injury, unable to breathe for himself, intubated with what we call ventriculostomy or a catheter going directly into the brain to relieve pressure, many times these patients do not survive. Even if they do survive and they seem to do well, they are often left with an invisible injury. For all practical purposes they look normal, but they may have long-term problems with memory, attention, irritability, sleep disorders, and things that really make it difficult for them to function the way they did before. Of course, we see this in the civilian population primarily at Duke, but it is also a huge area of concern in our returning veterans as well.
How does the process work?
Dr. Laskowitz: There are a lot of difficulties with these types of studies and one of the biggest difficulties is that to work most drugs have to be given acutely. In the case of progesterone or this current trial, we give it within an 8 hour time window and that sounds like a long time, but it is actually not because the patient cannot give informed consent. We have to find family or someone who is legally authorized to give informed consent, get the drug ready, and get them enrolled and started as soon as possible. The drug has to be actually initiated within 8 hours of injury and it is continuous infusion for 5 days. After that 5 day period, it is stopped and we just look at long-term outcomes and the ultimate endpoint is how they are doing at 6 months.
How many times over a 5-day period do they get this?
Dr. Laskowitz: It is a continuous infusion. It actually begins and is continuously infused intravenously for 5 days.
So it is like one of the blood bags you see?
Dr. Laskowitz: Exactly. It is actually on a micro pump that delivers it at a very specific rate based on their weight.
What does it do?
Dr. Laskowitz: It is interesting. Some of the initial data came from observations that female rats seemed to do better than male rats and progesterone is a normal hormone that is present in both men and women. It is associated with pregnancy and it is produced within the brain. Although no one knows exactly what it does, there is good evidence that it reduces inflammation. After brain injury, what will happen is that there will be this big inflammatory response, and like when you injure any area of the body, it will start swelling and that pressure could lead to herniation. The pressure can build up and cause the brain to force down upon itself because it is in an enclosed volume; there is no place for that pressure to be transmitted. The drug reduces the inflammation and the secondary neuronal injury. After neurons in the brain are injured, sometimes they go onto die a delayed death and are still salvageable, but if nothing is done they die over a period of hours or days, which is called apoptosis. Progesterone has been shown to decrease apoptosis and take those neurons which may go onto live or die and help promote survival.
Is it a challenge to get people enrolled in this since it has to be so quick after the accident?
Dr. Laskowitz: It is a huge challenge and I think it would be really important to see a new therapy come along, but because so many therapies have failed in the past there is often some reticence to bring new therapies to market. The clinical trials themselves are very difficult to do because car accidents may happen in the wee hours of the morning, on the weekends, and you really need to have an infrastructure that mobilizes on a moment's notice that could be at the hospital and get informed consent. Because it is severe traumatic brain injury, you cannot get informed consent from the patient; so you have to hopefully get relatives or someone who can give consent to even initiate them and there are often entrance criteria as well. So, they are very difficult studies to do. Steven did amazingly well from where he was initially. We go by what we call a Glasgow coma score, which is kind of the severity of the neurologic injury. He was essentially comatose, unable to breathe for himself, intubated. Where he is now, which is functional, is fantastic even though he has some minor residual problems. The caveat is we do not know if he got the drug or not and there is a lot of variability in recovery after TBI.
Can you describe his appearance when he came in? Can you see that swelling? Can you see the signs of it just by looking at them?
Dr. Laskowitz: No, you cannot. It is interesting that sometimes the patients who have the most brain injury superficially appear to look pretty good. That is they do not necessarily have facial swelling or even when you do CAT scan it could be normal. What happens is if you can imagine all of the axons, all of the wiring of the brain shears because the head rotates around itself creates an injury that we call DAI, or diffuse axonal injury. They can look normal and their CAT scan initially can be pretty unremarkable, but they could just be left with devastating neurologic injuries. So, you cannot really predict how much injury there is to the brain based on someone's superficial appearance. He looked pretty well in terms of superficial appearance and lacerations, but he had a very significant brain injury and was comatose when he came in; very severely impaired.
How does he compare to other TBIs?
Dr. Laskowitz: He did remarkably well, and you can imagine his mom who had this 21-year-old boy in the prime of his life who suddenly in an instant was in a coma with a life-threatening injury. He has done well but you have to realize at the time, we did not know whether he was going to live or die or whether it was even a survivable accident, but within a month he was out of the hospital and in rehab. Something I think we do not appreciate as much in the ICU is fully appreciating long term impairments. We see someone with a life threatening injury do really well and pat ourselves on the back, and it was certainly a success story, but often patients are left with long-term subtle deficits that really impair their ability to live as they did before. They could be problems with memory, with concentration, with fine motor skills, sometimes with irritability or mood swings, and this is very common after traumatic brain injury. It is one of the reasons it is so important that when we do the animal models to test new therapies. We try to model the same clinical problems that people have and that has not traditionally been done. It is one of the reasons why therapies sometimes do not translate to the clinical setting.
How is he doing now? Has he had some of those residual effects?
Dr. Laskowitz: I hate to use the word miracle, but he is doing miraculously well given where he was before. He is functional, alert, and interactive. I think if you met him, you would not know that he had just been through a life-threatening injury. There are some subtle problems that he might want to talk about. For example, he is tired a lot and much more fatigable than he was before. There may be some other subtle kind of emotional changes that he has had to struggle through, but this is a big disruption of your life. You could imagine you are 21 and suddenly your life is put on hold, so it has been a difficult time.
When did it happen?
Dr. Laskowitz: This happened June of last year. Within the first 6 weeks he was out of the hospital and in rehab, so he has actually done remarkably well. He may well have gotten the progesterone. The problem is that we do not want to bring our expectations to bear so obviously as a clinician, when you work with patients with bad traumatic brain injury you really want a new drug to come along and be effective, but that can influence how you manage patients and how you gauge their recovery. We are totally blinded, so I do not know if he got progesterone or not and he does not know. As a matter of fact, everybody is blinded until the end of the study where they will take out the blind and look at both groups.
Have you seen any other results that are comparable to this at all in the study?
Dr. Laskowitz: I think one of the frustrating things about traumatic brain injury is despite our best efforts to model who does well and who does not do well, we can have two people side by side who are the same age with about the same injury, and one might go onto have horrible brain swelling, herniate, and pass away and one may walk out of the ICU a few days later. There is a lot of variability in terms of how people do and I think a lot of that is due to your genetic background. Some people have a more robust inflammatory response. After an injury, their brain and their body just respond differently. So I would say that Steven is on the far end of the spectrum given how severe he was initially injured to where he is now.
He is not really the average, correct?
Dr. Laskowitz: No, he is certainly not.
How frustrating has it been for you over the last 20 years to not have something definitive to help people?
Dr. Laskowitz: It is hugely frustrating. I mean, you have to appreciate that many times we see young people in the prime of their lives. Traumatic brain injury tends to happen in 3 different age groups. The very young, and thankfully we do not see that, go to the pediatric ICU and often that is abuse or shaken baby. We see a lot of people in adolescence or their early 20s after car accidents or trauma and we see older people after falls. I do not want to give the impression that we do nothing; there is a lot that we do in the ICU. We provide supportive care and we support respirations, we have treatments that at least in the short-term can reduce pressures within the brain as the brain swells. However, it is extraordinarily frustrating that even as basic science advances and all these promising new therapies have come along, nothing has ever been shown to improve long-term outcomes. In many ways we lag behind different areas of the hospital, so I think we are close. There is sometimes reticence to bring new drugs to market because there is such a track record of failure that if companies are risk adverse, the chances are that they will not succeed. However, this progesterone trial is one of the few phase 3 trials that has very good early clinical data and hopefully in my lifetime we will have something better to offer.
How many make it to phase 3?
Dr. Laskowitz: The majority of compounds do not even make it phase 3. There is a bottleneck with promising compounds that seem to look good in animals, but they do not translate to clinical utility. There have been a few neuroprotective drugs that have made it to phase 2 but failed in phase 3 as well. So, very few actually make it to phase 3. To the best of my knowledge, this may be the only drug right now in phase 3 for traumatic brain injury.
Is it exciting to have something come along after all these hurdles to possibly make it to market at some point?
Dr. Laskowitz: Yes. There are a few exciting features about this. First of all, it is just a normal hormone so we know there is very little downside. There is a data and safety monitoring board with this trial as there are with all clinical trials, but it seems to be well tolerated. When you look at the risk benefit, although we do not know because it is blinded, there appears to be very little risk associated with it. It would really be a paradigm shift if we actually had something that we knew improved long-term outcomes. So yes, it would change everything to have a new drug. I think it would spur interest in more drugs to come along once that precedence is set as well.
How long do you think this phase 3 trial will last? I guess it all depends on until you can get enough participants?
Dr. Laskowitz: They are enrolling quite well. Duke is a site, but they have multiple sites throughout this country and internationally so they are hoping that in the next 6 months or so they will finish enrollment. This has been going on for a number of years. It often takes a while to get that infrastructure to effectively enroll people and you have to enroll an awful lot of patients to see a clear benefit so they needed over 1,000 patients, but they are within a few months of completing the study.
Anything else on the BHR that you think is important for people to know?
Dr. Laskowitz: I would like to leave people with that I think there is really dynamically changing landscape in traumatic brain injury. There will be new drugs whether it is progesterone or another drug hopefully in the near future and it is really important to fund the early research. The work, for example, is being done at Duke and other places as well looking at animal models of traumatic brain injury and new therapies. It's also important for people to want to perhaps participate in clinical trials because that is how the field moves forward.
FOR MORE INFORMATION, PLEASE CONTACT:
Daniel Laskowitz, MD, MHS Professor Medicine (Neurology) Neurobiology & Anesthesiology Director, Neurovascular Laboratories Duke University Medical Center (919) 684-0056
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