May 23, 200712:30 p.m. EDTM
Ladies and gentlemen, thank you for standing by and welcome to the Pediatric Seizure Study. At this time, all participants are in a listen-only mode. Later we will conduct a question and answer session. Instructions will be given at that time. As a reminder, this conference is being recorded. I would now like to turn the conference over to your host today, Mr. Bob Bock, Press Officer, NICHD. Please begin, sir.
Hi, thank you for joining us. This is Bob Bock, Press Officer for the National Institute of Child Health and Human Development. Welcome to the briefing. The briefing is sponsored by our institute, NICHD, part of the National Institutes of Health. In the briefing, we’ll describe the NIH-sponsored Pediatric Seizure Study. At the end of the call, reporters will have the opportunity for questions after the speakers have delivered their remarks. Joining us today are James Chamberlain, MD, Division Chief of Emergency Medicine at Children’s National Medical Center in Washington D.C., and principal investigator for this study; Jill Baren, MD, of the Division of Emergency Medicine, Department of Pediatrics, the Children’s Hospital of Philadelphia, Pennsylvania, and co-principal investigator of this study; Donald Mattison, MD, Chief of the Obstetrics and Pediatric Pharmacology Branch at the NICHD, which is sponsoring this study. And now I would like to turn it over to Dr. James Chamberlain.
Thank you. Good afternoon, thank you all for participating in this audio news briefing. I’d like to talk about three aspects of this study. First I’m going to describe status epilepticus. I am going to talk about current treatments that are available for status epilepticus. And then I’m going to talk about the study design.
So when we talk about status epilepticus, this is different than a typical seizure which lasts two to three minutes and then stops on its own. This is a continuous, unrelenting status of seizures in children, and it can be harmful or even fatal if it’s not controlled in a timely manner. It requires urgent, immediate treatment, usually in an ambulance or an emergency department. Even with the best treatments, seizures can be fatal. Status epilepticus affects between 50,000 and 60,000 children and adults every year in the United States. And four to eight children per thousand will experience status epilepticus before the age of 15.
Our current treatments consist of, currently our first-line treatments are two medications called Diazepam and Lorazepam. They are both in the same class of medicines called benzodiazepines. Diazepam has been approved by the FDA for use in both adults and children. On the other hand, Lorazepam has only been FDA approved in adults, but it’s widely used in children at the discretion of the treating physician. That’s what we call off-label use. Once the drug has been approved by the FDA for one use, physicians can use their judgment and use it for other uses that they think it might be helpful.
It’s important to note that both Diazepam and Lorazepam have been used for over 20 years in both pediatrics and adults, and they both do a nice job of stopping seizures and they both appear to be safe. The issue is that we don’t know which one is better. There may be subtle differences between the two medicines, and there have been some studies done in the past, which have not provided definitive evidence as to which medicine is better, so we want to perform the definitive study and hold these medications to the highest standard to make sure that children are receiving the most appropriate medication course for status epilepticus.
I will now talk about the study design. Eleven University Hospitals across the United States have agreed to participate in this study. Children who present to emergency departments in status epilepticus, and who meet the study criteria, will be randomly assigned to receive one of the two medications, using a computer program. This is different than routine emergency care, where the physician chooses the medication. We use a process called randomization to reduce the chance that human bias plays a role in how the medications are assigned to the patients by the doctors. So the doctors have all agreed to participate in this study and to use the randomization process, rather than their own choice, because they know that this is the best way to figure out which medicine is better.
Now keep in mind that we need to administer the medication within five minutes of arrival in the emergency department, so things have to happen quickly. Sometimes treatments need to be administered in ambulances as well. Because we need to treat the seizures rapidly, we don’t have time always to talk to parents about the study during the seizure episode. Now I’d like to turn this over to Dr. Jill Baren to talk about how we plan to enroll patients in this study.
Thank you, Jim, and good afternoon to everyone. You’ve already heard from Dr. Chamberlain that status epilepticus is a life-threatening condition, and in some cases, can even be fatal. And I’d like to use that concept as the backdrop for what I’m going to talk about next, which is an explanation of the informed consent procedures associated with the Pediatric Seizure Study.
Now ordinarily, when we set out to do a research study, researchers will ask parents or guardians for their permission to enroll a child in the research, by first explaining the study details and procedures, its potential risks and benefits and alternatives, and of course, will only enroll the child after the parent agrees. Why is the Pediatric Seizure Study different in this capacity? Well, our consent procedures are different because of the need for rapid treatment for life-threatening seizures. Under these conditions, children with status epilepticus that present to study hospitals will be randomly assigned to receive either Diazepam or Lorazepam, and parents won’t be told about the study or asked for their permission to enroll the child, until after the child has been stabilized. Now this sequence of events is a little different from what would happen in a clinical situation in an emergency department that is not taking part in the study. Under those conditions, a treating physician would decide first whether the patient received Lorazepam or Diazepam. In the Pediatric Seizure Study, a computer program will decide which drug the child receives. So the idea is to assign the drug without any preference, to avoid introducing any potential bias into the study procedure. At the end of the study, roughly equal numbers of children will have been assigned to receive each drug, and a large enough number of children will have been studied, in order to allow the researchers to draw definitive conclusions about each medication. So again to reiterate, the purpose of this study is to find which of the two drugs provides the safest, most effective treatment for children with status epilepticus. And when the study is finished, we will then have a strong, factual basis for the treatments that clinicians prescribe.
Now after the doctor has made sure that a child has been treated and stabilized for status epilepticus, then a representative of our study team will contact parents or guardians to let them know that the child has been enrolled in the study. And at that time, the details of the study will be explained to the parent, and the parent can then choose whether to allow the child to continue, or at that time can withdraw the child from the study, and investigators will fully respect that decision. If the parent agrees to continue in the study, then small blood samples will be taken from the child, and the parent will be interviewed by phone approximately 48 hours later, and then 30 days after the child is enrolled, to ask about the child’s condition.
Now there are some very important safety considerations that have been conducted in conjunction with our trial. An independent review board or research review committee at each hospital that’s participating in the study will actually oversee the study, and will ensure that all of our procedures are in compliance with the highest ethical and safety standards. There is another independent review body that will look for overall trends in the study data, such that if it becomes apparent that one drug is more effective than the other, the study will be ended early. I also want to point out that we have consulted a wide range of ethicists of pediatric and research experts and government officials about this study to ensure that we protect patient’s safety.
In conjunction with these unique consent procedures in our study, we have designed a comprehensive public information campaign to inform the public about our study in the various communities where it will be performed. Now this activity consists of community meetings and other outreach activities to provide information about the study to all interested families. This deems that ahead of time, parents and guardians may decline to have their child take part in the study, either before the child experiences an emergency seizure, or even during an episode of an emergency seizure, when they accompany their child to the emergency department. Families will be given every opportunity to decline participation before a medical emergency arises. If a child resides in the study area, and his or her parents do not want the child to participate, then parents will be able to contact the center in their area to make their wishes known. Children who decline to participate in the study will still receive the same exact medical care for their seizure as those who do choose to participate in the study.
The study will begin in stages. Participating study sites will vary as to when they will begin, and when they will begin informing their communities that the study will take place. Right now, all of the study sites are undergoing a thorough review process before beginning. Some sites may begin within the next few weeks, whereas other sites are not expected to begin for several months. Parents can opt out of the study, depending on when the individual site has completed the review process. Once the study site has completed the review process, it will again hold these community meetings and outreach activities, and post other notices about when the study is ready to begin in their area. At that time, procedures will be in place for parents and guardians to contact their local site that they do not wish to have their child participate.
If parents and guardians are interested in finding out when their local site might be conducting such activities, or when the study will be starting, then they will be able to contact the seizure study personnel in the emergency department of the participating hospital in their area.
And now I’d like to have Dr. Mattison conclude the remarks for the briefing.
Good afternoon. My name is Don Mattison. I’d like to extend and echo the welcome of Drs. Chamberlain and Baren from the NIH. I’d like to describe briefly the background that led us into this study and the reasons that we’re conducting it. NICHD is funding this study of seizure treatments under the provisions of the congressionally enacted Best Pharmaceuticals for Children’s Act. This Act lays out the role that NIH, NICHD, and the FDA play in determining which drugs need to be tested in children, and how those tests are put in place.
Early after the Best Pharmaceuticals for Children’s Act was enacted, we convened a group of experts in pediatrics and in pediatric seizure disorders, and asked them to explore with us the drugs that needed to be tested in children. In addition, we also engaged experts from the various institutes and centers within the NIH, as well as within the FDA, to engage in similar discussions. And the outcome of those discussions was the need to provide much greater information about these two drugs in treatment of children with status epilepticus. So we have developed the study that Drs. Chamberlain and Baren described.
You might ask why, given that these drugs have been around for 20 years, we need to test them. And it’s true for these drugs, as well as for many other drugs, that they’re used in children often without detailed evaluations, the same types of detailed evaluations that are conducted in adults. And these two drugs fall into that category. We know that it’s important to test drugs in children, even if they’ve been tested in adults, because children are very, very different in the way that they respond to medications, and the way that the medications are eliminated from their body. So based on the process that was put in place by Congress in 2002, recognizing the need to provide substantially greater testing of drugs in children, and the important public health considerations that surround children who have status epilepticus, including the substantial both morbidity and mortality, these two drugs have been high on our list for evaluation.
I’d like to now end this part of the discussion of the background for our study, and open this up for questions.
Thank you. One moment for the first question. The first question comes from Bob Davis with USA Today.
Hi, thanks for taking my question. I’m wondering what happens when care has been started in the field, when people come in by ambulance and they’ve already been administered some drug, or does this extend into the field?
Yes, thanks for that question. This is Dr. Chamberlain again. If a patient has received a benzodiazepine medication in the pre-hospital setting, they would not be eligible for enrollment in the study.
Our next question comes from Katherine Campbell, freelance journalist.
Yes, thanks for taking my call. Can you please tell me just a little bit more about how serious this issue is, how common these kinds of seizures are in children? Thank you.
This is Dr. Chamberlain again. In busy emergency departments across the country, it’s not unusual to see one of these patients every day, or every couple days, so it’s very common. Again, there are 50,000 to 60,000 episodes of status epilepticus a year in the United States. That includes adults and children. And four to eight children per thousand will experience an episode of status epilepticus before their 15th birthday.
Our next question is a follow-up from Bob Davis.
Thank you. How many patients do you anticipate enrolling in this, and is this the first time this computer has been used to randomize treatment like this?
This is Dr. Chamberlain again. Our initial estimate of sample size would be about 240 patients, so 120 receiving Diazepam, and 120, approximately, receiving Lorazepam. We plan to do analysis at the mid-point of the study to see if our original sample size estimates hold, or whether we need to adjust them. We may end up being able to do the study with fewer patients, depending on the results at the mid-point. And the second question again was?
Has this computer program been used previously to randomize care this way?
Oh, sure. Our statisticians routinely use programs like this to randomize patients for research care, yes.
I’m showing no further questions at this time.
I’d like to remind the people who called in, or inform the people who have called in, a news release and an accompanying set of questions and answers is available on the NICHD Web site at www.nichd.nih.gov. If there are no further questions, we’ll end the briefing here. Thanks very much.